TW200424198A - Imiidazopyridine compounds as 5-HT4 receptor agonists - Google Patents

Abstract

This invention provides a compound of the formula (I): , wherein R1 represents a hydrogen atom or a halogen atom; R2 represents a methyl group or an ethyl group; R3 represents a branched alkyl group having from 3 to 6 carbon atoms or an alkyl group having from 3 to 6 carbon atoms substituted by an alkoxy group having from 1 to 6 carbon atoms; with the proviso that when the terminal carbon atom of said alkyl group is substituted by said alkoxy goroup, said alkyl group is a branched alkyl group; and pharmaceutically acceptable salts thereof. These compounds have 5-HT4 receptor binding activity, and thus are useful for the treatment of gastroesophageal reflux disease, non-ulcer dyspepsia, functional dyspepsia, irritable bowel syndrome or the like in mammalian, especially humans. This invention also provides a pharmaceutical composition comprising the above compound.

Description

200424198 (ii) Description of the invention: [Technical field to which the invention belongs] The present invention relates to novel imidazopyridine compounds. These compounds have 5 · T4 receptor agonist-binding activity 'and therefore can be used in mammals, especially humans' to treat or prevent gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorders, Insomnia I, malformation, irritable bowel syndrome, constipation, indigestion & esophagitis, gastroesophageal disease, nausea, central nervous system disease, bismuthheimer's disease, cognitive impairment, vomiting, Migraine, neurological diseases, pain, ischemic stroke, anxiety, cardiovascular disorders, etc. The present invention also relates to pharmaceutical compositions containing the aforementioned compounds. [Prior Art] Serotonin (5-ΗΤ) receptors are known to have a variety of Subtypes, such as 55Τι, 5-ΗΤ2, 5-ΗΤ3, and 5-ΗΤ4. These 5_ΗΤ4 receptors are disclosed, for example, in European Music Journal 146 (1988), 187-188, and Naunyn-Schmiedeberg's Pharmacological Archives (1989) 340: 403-410. 5-HT4 receptor modulators (such as agonists and antagonists) are known to be useful in the treatment of a variety of diseases such as gastroesophageal reflux disease, gastrointestinal diseases, gastrointestinal disorders, non-ulcerative dyspepsia, Functional indigestion , Irritable bowel syndrome, constipation, indigestion, esophagitis, gastroesophageal disease, alpha nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, vomiting, migraine, neurological disease, pain and heart Vascular disorders such as heart failure and arrhythmias. (Refer to TiPs, 1992, 13, 141; Ford APDW ·, et al., Comprehensive Medical Research, 1993, 13, 633; Gull iks on GW ·, et al., Comprehensive Drug Derivatives, 1992 26,405; Richard M. Eglen et al., TiPS, 1995, 16,

O: \ 87 \ 8713l.DOC 200424198 391; Bockaert J. Et et al., CNS Drugs, 1, 6; Romanelli M. N. et al., Arzheim Forsch · / Drug Research, 1993, 43, 913; Kaumann A. et al. Human, Naunyn-Schmiedeberg's, 1991, 344, 150; and Romanelli M.N. et al., Arzheim Forsch · / Drug Research, 1993, 43, 913). A variety of imidazopyridine compounds are known as 5HT receptor antagonists or agonists. For example, Japanese Patent Publications H01-258,674 and H02-643,274 disclose imidazopyridine compounds as 5HT receptor antagonists. WO 96/05 166 discloses imidazopyridine compounds as 5HT4 exciters. WO 92/15593; USP 5,260,303; USP 5,604,239; USP 5,5 91,749; USP 5,219,850; USP 5,434,161; USP 5,13 7,893; USP 5,196,547; and EP 504679 disclose a variety of imidazopyridine compounds as 5HT3. Body antagonist. WO 94/08998 discloses imidazopyridine compounds as 5HT4 receptor antagonists. In addition, the synthesis of imidazopyridine compounds for different uses is described in JP 2001/6877; WO 01/5763; WO 99/50247; WO 97/27852, WO 9738665, and EP 274867. It is desirable to provide a 5HT4 receptor agonist which has higher 5-HT4 receptor agonist activity. A variety of imidazopyridine 5-HT4 receptor modulator compounds are disclosed in U.S. Application No. 60 / 343,371, filed October 22, 2001. Particularly, the compound represented by the following formula is disclosed in U.S. Application No. 60 / 343,371: O: \ 87 \ 87131.DOC -8- 200424198

Compound A Compound B QT prolongation is known to cause lethal arrhythmia in Torsades de pointes (TdP). The ability to prolong the duration of the cardiac action potential was identified as a function of the HERG potassium channel. For example, drugs that are prolonged by qT such as Cisapride and Terfenadine are known as potent HERG potassium channel blockers (Expert Pharmacological Therapy; 2, pp947_973, 2000). It is therefore desirable to provide a novel 5HT4 selective agonist that can be used for the treatment of a variety of diseases, such as gastroesophageal reflux disease, gastrointestinal disease, gastrointestinal disorders, non-ulcerative dyspepsia, functional dyspepsia, Irritable bowel syndrome, constipation, indigestion, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, vomiting, migraine, neurological disease, pain and cardiovascular conditions such as Heart failure and arrhythmia; and its inhibitory activity on HERG potassium channels is reduced. [Summary of the Invention] It is unexpectedly discovered today that the compound broadly covered by US Patent No. 60 / 343,371 is a 5HT4 selective agonist, which can be used to treat a variety of diseases through systemic administration, such as gastroesophageal reflux disease, gastrointestinal Road disease, premature disturbance of gastric motility, non-ulcerative dyspepsia, functional dyspepsia, irritable bowel syndrome, constipation, indigestion, esophagitis, gastroesophageal disease, nausea, middle

O: \ 87 \ 87131.DOC 200424198 Central nervous system disease, neurological disease, pain, schizheimer's disease, cognitive impairment, alpha vomiting, migraine, and cardiovascular disorders such as heart failure and arrhythmia, and HERG The inhibitory activity of the channel is reduced. The inhibitory activity of HERG channels is estimated from the affinity of HERG-type potassium channels. The affinity of type-releasing channels is studied by testing [3H] dofetilide binding. [3H] dofetilide binding can inhibit the HERG channel. Inhibitory activity (European Journal of Pharmacology, Gaja, P 7 148 2001). The compounds with low [3h] polyguinea-binding activity were selected and evaluated in the iHERG assay to check the activity in the herg channel. The introduction of a branched group into a fixed ring nitrogen atom can promote a powerful 5-HT4 receptor exciter: sex, accompanied by a decrease in the inhibitory activity of the HERG channel. The compounds of the present invention exhibit good low absorption, good distribution, reduced drug-drug interactions, and metabolic stability. The present invention provides a compound of formula (I):

(I) where R represents an iron * atom or an _ atom; R2 represents a fluorenyl group or an ethyl group; R represents a branched alkyl group not containing 3 to 6 carbon atoms or substituted with an alkoxy group containing 1 to 6 carbon atoms An alkyl group containing 3 to 6 carbon atoms;

O: \ 87 \ 87131.DOC • 10-200424198, the alkyl group is a Nita alkyl group whose terminal carbon atom is substituted with the alkoxy group for a branched alkyl group; and a pharmaceutically acceptable salt thereof. The Mizolopyridine compound of Maoyue has a 5-T4 receptor agonist activity so it can be used to treat or prevent diseases caused by 5-receptor active mediators, accompanied by a decrease in the inhibitory activity of the HERG channel. Thus, the present invention provides a pharmaceutical composition for treating a disease caused by a 5-HT4 receptor active vector in a mammalian body, comprising administering to the animal body a therapeutically effective amount of a compound of formula (I). In addition, the present invention provides a method for treating gastroesophageal reflux disease, gastrointestinal diseases, dyskinesia, non-ulcerative dyspepsia, functional dyspepsia, irritable bowel syndrome, constipation, indigestion, esophagitis, stomach Esophageal disease, chewing ~, central nervous system disease, Alzheimer's disease, cognitive impairment ... Regional vomiting, migraine, 4 menstrual disorders, diseases, pain, and cardiovascular disorders such as heart, visceral failure, and arrhythmia A composition comprising a therapeutically effective amount of a compound of the formula imidazopyridine or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. In addition, the present invention provides a method for treating a condition in a mammalian body by a ΗTA receptor active agent, comprising administering to the individual a therapeutically effective amount of a compound of formula ⑴. In addition, the present invention provides a method for treating the aforementioned diseases. In addition, the present invention provides the use of a compound of formula (I) for the manufacture of a medicament, which is used for treating or preventing a disease mediated by the 5-T4 receptor activity in a mammal. The disease of the 5-ΗΤ4 receptor active vector is the disease or disease described above.

O: \ 87 \ 87131.DOC -11-200424198 [Embodiment] As used herein, the term "halogen atom" means fluorine, chlorine, bromine and iodine, preferably fluorine or gas. As used herein, the term "alkyl" means a linear or branched saturated group including, but not limited to, fluorenyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second Butyl, third butyl, isopentyl, neopentyl, third pentyl or isohexyl. As used herein, the term "branched alkyl" means that the branched chain saturated group includes (but is not limited to) isopropyl, isobutyl, second butyl, third butyl, isopentyl, neopentyl Base, third pentyl or isohexyl. As used herein, the term "alkoxy" means alkyl_〇_ includes (but is not limited to) methoxyethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy Group, second butoxy, third butoxy. The term "treatment" is used herein to mean to reverse, alleviate, or inhibit the disease or condition to which the term applies, or to perform or prevent the treatment of symptoms of one or more such conditions or diseases " The term "treatment" is defined as before. As used herein, the term "modulator" sexually regulated compound, excimer, means that it can directly or indirectly affect the Ri atom in the receptor active compound ⑴. Excitants, antagonists, ligands, substrates and enzymes. R preferably represents a hydrogen atom or a gas atom; more preferably chlorodibutyl ethyl; and in the compound of formula (I), R3

In the present invention, R3 preferably represents isobutyl, and is substituted with methoxy. Individual compounds are:

O: \ 87 \ 87131.DOC • 12-200424198 5-Amino_N _ [(1-isobutylpiperazinyl 4-methyl) methyl] -2-methylimidazo [, 2-a] Ebite_8 _Juniamine and its salts. Preferred individual compounds of the present invention are: 5-amino-6-chloro-N _ {[1_ (3 3 -Tiangan ^ gan, mono, monomethylbutyl) piperidin-4-yl] methylbull 2 Ethylimidazo [丨, 2 ^] pyridine-8-carboxamide and its salts. Preferred individual compounds of the present invention are: 5 its knees 6 ′ gas _2_ethyl · N _ {[ι · (2_methoxy_2_methylpropyl) yellol methyl} mizo [ 1,2_a] pyridine-8-carboxamide and its salts. Preferred individual compounds of the present invention are: amine heptachloro_2_methylzan {[1_ (2-methoxy_2_methylpropyl) "4-yl] methyl} imidazo [丨,] 々 ] Pyridine-8-carboxamidine and salts thereof. Preferred individual compounds of the present invention are: ,, 5-amino-6-chloro_N-[(1_isobutylpiperidine_4_yl) methyl ] 々 · methylimidazo-H, 2-a] pyridine-8-carboxamidine and its salts. General Synthesis The imidazopyridine compounds of formula (I) of the present invention can be prepared via a variety of synthetic methods. The preparation method of the compound can obtain the corresponding acid acid compound (111) through the ammonium acid salt compound ("), followed by the coupling reaction between the compound ⑽ and the amine compound (IV), as shown in the following reaction figure 1. Reaction Figure 1:

O: \ 87 \ 87131.DOC -13- 200424198 〇

〇i)

OH h2n

(III)

(Where R 'is a k-alkyl group or a φ group; and all other symbols define the reaction. In Figure 1, the' sulfonium salt compound W first accepts the saponification of the ester residue at the 8-position and then acidifies to obtain the corresponding fluorene. Acid hydration: The post-compound ⑽ can be coupled with amines to combine with ___wow and cut: 物 (I) 〇 ° Saponification and acidification can be performed by conventional procedures. In a typical procedure, saponification is performed by using sodium hydroxide or hydroxide Lithium is treated with an appropriate reaction inert solvent. Suitable solvents include, for example, alcohols such as methyl, ethanol, hydrazone, butanol, 2-methoxyethanol, and ethylene glycol; bonds such as tetrahydrothran (thf), and Dimethoxyethane_ and, 4 · Dioxane; Painted hydrocarbons such as gas-formed 'dichloroethane and 1,2-digasethane; amines such as Ν, Ν, dimethylamine (Qing) and trimethylamine hexamethylene diacetate; and sulfite gf to § sulfoxides such as dimethyl sulfoxide (DMSO). Such anti-O: \ 87 \ 87131.DOC _ 14- 200424198 should be At _20 to loot :, usually at a temperature of 20 ° C to 65 ° c, for 30 minutes to 24 hours, usually 60 minutes to 10 hours. In a typical procedure, the acidification is performed by Use dilute hydrochloric acid or 10% aqueous citric acid in an appropriate reaction inert solvent such as water at a temperature of -20 to 65 ° C, usually 0 ° c to 30 ° C, for 30 minutes to 10 hours, and usually 3 0 minutes to 2 hours. The coupling reaction can be performed in a reaction inert solvent in the presence of a suitable condensing agent. Suitable condensing agents include 1,1'-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), Dicyclohexylcarbodiimide (DCC), water-soluble carbodiimide (wsc), 2-ethoxyethoxyquinyl-1,2-dihydrojunline, benzotrisialyl_ See ( Dimethylamine) hexafluorophosphate scale (BOP), azodicarboxylic acid diethylacetate · triphenyllin, gas-based diethylacetate (DEPC), diphenylscale azide (dppa), Bromotripyrrolidinyl hexafluorophosphate scale (PyBrop [registered trademark]), gas (2-keto-3-oxazolidinyl) phosphinic chloride (BOPC1), benzotriazol-1-yl-oxyl _ 参 _ Slightly octyl-hexafluorophosphate scale (PyBOP), 2- (1-pyrene-benzotrimethylene-1-yl) -1,1,3,3-tetrafluorenylhexafluorophosphate urea radium (HBTU) and ethyl chlorophosphonate. Suitable inert solvents include aqueous or non-aqueous organic solvents. Agents such as THF, DMF, 1,4-dioxane, acetone, DME, and acetonitrile; and hydrocarbons such as chloroform, monochloromethane, and 1,2-dichloromethane (preferably dichloromethane) ). This reaction can be performed at a temperature of -20 to 80 ° C, usually 0 ° C to 30 ° C, for 30 minutes to 100 hours and usually 5 hours to 24 hours. Reaction Diagram 2 z is used in Reaction Diagram 1 as The carboxylate compound of the starting material can be prepared in the following reaction steps: O: \ 87 \ 87131.DOC -15- 200424198

〇

In Reaction Figure 2, the acid salt compound (V) (where r is a C13 alkynyl group and a redundant element; and the amine group is protected by isopentyl group) can be reacted with ammonia to obtain the compound (VIII ). This reaction is usually carried out in a sealed tube. The reaction can be carried out in a suitable reaction inert solvent such as methanol, ethanol, propanol, butanol, 2-methoxyethanol and THF. The reaction is between 30 and 150. (: Usually 5 (rcs1007 temperature for 30 minutes to 24 hours, usually 30 minutes to 12 hours. When R1 is an i atom, the compound (VIII) uses _ prime or N- Halogenated succinimide or selectfluor (registered trademark), where L is the compound (IX) where Ri is a halogen atom. This reaction can be performed appropriately

O: \ 87 \ 87131.DOC -16- 200424198 The reaction is performed with inert solvents, such as solvents such as carboxylic acids (such as acetic acid, propionic acid, and butyric acid) 'and functional hydrocarbons such as chloroform, dichloroethane, and 1? 2. Dichloroethene; sulfonamides such as DMF and / or trimethylamine methyl phosphate; sulfoxides such as; acetonitrile; benzene, methylbenzene, xylene; and pyridine. This reaction can be performed at 0 to 80 ° C, usually 25 to 7 ° C (TC temperature for 5 minutes to 24 hours, usually ^ minutes to 8 hours. Then, the compound (1) accepts the deprotection of the amine protecting group And obtained, compound (X). Deprotection can be carried out in the presence of a base (such as potassium tert-butoxide, sodium ethoxide and sodium hydroxide) or an acid (such as hydrochloric acid and sulfuric acid). Deprotection can be performed in an appropriate reaction An inert solvent, such as methanol, is carried out at a temperature ranging from 25 to 80 ° C, usually from 50 to MC, from 10 minutes to hours, usually from 30 minutes to 10 hours. χι) where χ is a halogen reaction to obtain a compound (II) and compound (χπ). This reaction can be in a 2-halogenated aldehyde or a halogenated ketone (compound (χυ) in the presence of D, in an appropriate reaction inert solvent such as methanol , Ethanol, propanol and butanol at a temperature range of 25 to 12.0, usually 50 to 65 t, for 8 hours to 72 hours, usually 8 hours to 24 hours. The compound (II) is obtained ) And compound (χπ) are obtained by conventional separation techniques to obtain Compound (II). Appropriately known separation techniques include silica gel column chromatography. In addition, the starting compounds of formula (V) are known or can be prepared from known compounds according to known procedures. Reactions Figure 3: Compound (Γ) (Compound ⑴ where ... is hydrogen) can be prepared via Compound ⑴ where R is a halogen atom and undergoes a catalytic hydrogenation reaction.

O: \ 87 \ 87131.DOC -17-

200424198 Reaction In Figure 3, catalytic hydrogenation can be performed in the presence of hydrogen or a hydrogen source. Chlorine sources such as ammonium formate, triethylsilane, and appropriate metal-containing catalysts such as palladium, platinum, nickel, platinum oxide, and germanium are reacted in an appropriate inert solvent such as methanol. . A preferred catalyst is palladium / carbon. This hydrogenation can be carried out at a temperature ranging from 20 to 10 (rc, usually from it to the range of ⑽⑽) for 5 minutes to 48 hours, usually 30 minutes to 2 hours. Reaction Figure 4:

In reaction 4, compound (VI) is reacted with ammonia to obtain compound (νπ). This reaction is usually carried out in a sealed tube. This reaction can be carried out in a suitable reaction inert solvent. Suitable solvents include, for example, alcohols such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and ethylene glycol; ethers such as tHf, DME, diethyl ether, diisopropyl ether, diphenyl ether, and 1,4 _Dioxane; _Hydrocarbons such as chloroform, dichloroethane, and 1,2-dichloroethane; ammoniums such as DMF and hexamethylphosphonium triammonium phosphate; sulfoxides such as DMSO; acetonitrile; benzene , Toluene, xylene; and Yongding. This reaction can range from 30 to 150, usually 50. 〇 to 100. (: The temperature in the range is 30 minutes to 24 hours, usually 30 minutes to 12 hours. Compound (II) can react with compound (XΙ) via compound (VII) under appropriate conditions. O: \ 87 \ 87131.DOC- 18-200424198. This reaction can be carried out in a suitable reaction inert solvent such as methanol. This reaction can be performed at 25 to 65 ° C, usually 50 ° C to 65. (: temperature in the range of 30 minutes to 48 hours It is usually 30 minutes to 12 hours. Reaction Scheme 5: Nicotinate compounds (v,) and (VI) used as starting materials of Reaction Schemes 2, 4 and 6 can be prepared in the following reaction steps.

In reaction scheme 5 ♦, pyridine compound (XIII) in which 2 is _ prime can react with ammonia to obtain compound (XIV). This reaction is usually carried out in a sealed tube. This reaction can be carried out at a temperature in the range of 50 to 20 ° C, usually from 0.001 to 160 ° C, for a period of 30 minutes to 24 hours, usually for a period of 30 minutes to 12 hours. Compound (χιν) uses a fluorene-based gas as different Pentamidine is treated in the presence of a base such as diisopropylethylamine, triethylpyridine, and monomethylpyridine to obtain a mixture of compounds (xv). This reaction can be carried out in a suitable reaction inert solvent. Suitable solvents include, for example, functional hydrocarbons such as chloroform, dichloroethane, and u-dichloroethane.

O: \ 87 \ 87131.DOC -19- 200424198 should be -20 to 50 ° C, usually -lot to 3 (TC temperature range for 30 minutes to 24 hours, usually 30 minutes to 10 hours Compound (χν) is treated with an alkali metal such as n-butyllithium, and then treated with an alkyl haloformate such as chloroform, ethyl or + g, and chlorine to obtain compounds (ν ') and (νΐ). The reaction may be carried out in a suitable reaction inert solvent. Suitable solvents include, for example, ethers such as THF, DME, diethyl ether, diisopropyl ether, diphenyl ether, and dioxane. Such a reaction may be performed at -100 to 50. ° C, usually in the temperature range of -100 to 20 ° C, for 5 minutes to 24 hours, usually 15 minutes to 8 hours. In addition, the starting compounds of formula (XIII) are known or can be prepared according to the skill Preparation of known compounds by known procedures, such as Heiv · chim. Acta (1976), 59, 229-35, Journal of the Chemical Society, Perkin Trans · 1 (1996), 5 19-24, and the Journal of the Chemical Society 'Chemical Newsletter (1988), 1482_3. Reaction Scheme 6: The carboxylic acid ester compound (II) used as the starting material in Reaction Scheme 1 can be used in the following reaction steps. Equipment.

O: \ 87 \ 87131.DOC 20- 200424198

In reaction Figure 6, the nicotinate compound (v,) where R is ci 3 alkyl or benzyl and Z is halogen, and the amine group is protected by isoamyl, the compound (v,) can react with ammonia Compound (IX) is obtained. This reaction is usually carried out in a sealed tube. This reaction can be carried out in a suitable reaction inert solvent such as methanol, ethanol, propanol, butanol, 2-methoxyethanol, and tetrahydrofuran (THF). This reaction can be carried out at a temperature in the range of 30 to 150C, usually 50 ° C to 100 ° C, for 30 minutes to 24 hours, usually 30 minutes to 12 hours. Then, the compound (ιχ) is deprotected by protecting the amine group to obtain the compound (X). Deprotection can be performed in the presence of a base (such as potassium second butoxide, sodium ethoxide, and sodium hydroxide) or an acid (such as hydrochloric acid and sulfuric acid). Deprotection can be performed in a suitable reaction inert solvent such as methanol, at a temperature in the range of 25 to 80C, usually 50 to 65 ° C, for 10 minutes to 24 hours, usually 30 minutes to 10 hours. Compound (X) can then be reacted with compound (XI) to obtain compound (π) and compound (XII). This reaction can be carried out in the presence of 2-halogenated aldehyde or 2-halogenated ketone (compound (XI)) in a suitable reaction inert solvent such as methanol, ethanol, propanol and butanol, at 25 to 120. (:, Usually 5 (temperature from TC to 65t in the range of 8 O: \ 87 \ 87131.DOC -21-200424198 hours to 72 hours, usually 8 hours to 24 hours. The resulting person (Π) and compound The mixture of (XII) is subjected to conventional separation techniques to obtain compound (II). Suitable conventional separation techniques include silica gel column chromatography. Reaction Figure 7

⑴ (wherein R'gCi · 3 alkyl group and all other symbols are as defined above) In Fig. 7, the carboxylic acid compound (111) can be coupled with an amine compound (χνι) to obtain an imidazopyridine compound (XVII). Compound (XVII) then undergoes a deprotection reaction of a piperidine ring nitrogen atom protecting group, followed by alkylation to obtain an imidazolide compound (Γ).

O: \ 87 \ 87131.DOC -22- 200424198 The coupling reaction can be performed in a reaction inert solvent in the presence of a suitable condensing agent. Suitable condensing agents include 1, Γ-carbonyldiimidazole (CDI), diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), water-soluble carbodiimide (WSC), 2- Ethoxy-N-ethoxy-Ethyl-1,2-dichlorojunlin, phenylammonium 3-oxen-1-oxo- (dimethylamino) hexafluorophosphate scale (BOP), azobis Diethyl carboxylate-triphenylphosphine, diethyl cyanophosphonate (DEPC), diphenylphosphonium hydrazide (DPPA), bromotriethyl stilbene hexafluoroinhibitor phosphonium (PyBrop [registered trademark] ), Fluorene (2-keto-3-pyrazolidinyl) phosphinic acid phosphonium chloride (B0PC1), benzotriazol-1-yloxy-phenyl-pyrrolidinyl-hexafluorophosphate scale (PyBOP), 2- (1-fluorene-benzotriazol-1-yl) -1,1,3,3-tetramethylhexafluorophosphate urea hydrazone (HBTU) and ethyl chloroformate. Suitable reaction inert solvents include aqueous or non-aqueous organic solvents such as THF, DMF, 1,4-dioxane, acetone, DME, and acetonitrile; and i-hydrocarbons such as chloroform, dichloromethane, and 1,2-dichloroethyl Alkane (preferably dichloromethane). This reaction can be carried out at a temperature of -20 to 80 ° C, usually 0 ° C to 30 ° C, for 30 minutes to 100 hours, usually 5 hours to 24 hours. The amine compound thus obtained can be deprotected by an amine protecting group to obtain a compound (XVIII). Deprotection can be performed using a variety of standard procedures known to those skilled in the art (eg, "protection of hydroxyl and amino groups", organic synthetic protective groups, 2nd edition, edited by T. W. Greene and PGM Wuts, John Wiley & Sons, 1991, pp. 10-142, 309-405). The alkylation of the amine < group of the piperidine ring can then be performed under conventional conditions. The compound can be in the presence of a base such as diisopropylethylamine, triethylamine, trimethylamine, dimethylbenzene, bell carbonate, sodium bicarbonate, sodium carbonate, etc. in a reaction inert solvent such as dichloromethane, THF Or DMF, at about 0 ° C to about 100 ° C, use a suitable alkyl halide (R6-Z) to treat O: \ 87 \ 87131.DOC -23- 200424198 for about 5 minutes to about 48 hours. Reaction Figure 8: Amine compound (XXIII) in which Ra and Rbg Ci_4 alkyl groups and Re are Cb6 alkyl groups can be prepared in the following reaction steps.

Rb 〇 「Ra rc3o + .bf4 ·

In Reaction Scheme 8, a piperidine compound (XIX) is reacted with an epoxy compound (XX) to obtain a hydroxy compound (XXI). This reaction can be performed in a suitable inert solvent (e.g. THF, DMF, acetonitrile, dichloromethane, 1,2-dichloroethane, DMSO, isobutanone, methanol, ethanol, propanol, butanol, isobutanol, The second butanol and the third butanol) are performed at a temperature of -50 to 250 ° C, usually 0 ° C to 200 ° C, for 30 minutes to 100 hours, usually 1 hour to 80 hours. This reaction can be carried out in the presence of metal halides such as sodium sulphide, ehuazine and lithium moth. The conversion of the hydroxy compound (XXI) to the alkoxy compound (XXII) can be carried out by a conventional method. The alkylation of the hydroxyl group can be performed under conventional conditions. The compound can be in the presence of a base (such as sodium oxide, sodium ethoxide, potassium third butoxide, sodium hydride or potassium hydride, etc.) in a reaction inert solvent such as diethyl ether, DME, DMSO, THF or DMF at about 0 ° C. To about 200 ° C, usually 0 ° C to 200 ° C, treated with a suitable alkyl halide (R6-Z) for about 5 minutes to about 100 hours, usually 1 O: \ 87 \ 87131.DOC -24 -200424198 hours to 80 hours. The hydroxy compound (XXI) can be treated to obtain a compound (χχπ). This reaction can be performed in an appropriate inert solvent (such as 1,2-dichloromethane, dichloroethane, benzene, toluene, and nitromethane) at _50 to 20 (TC, usually… (: to丨 ⑼ ^ The temperature is in the range of 30 minutes to 100 hours, usually i hours to 80 hours. The resulting person (XXII) receives the deprotection of the amino protecting group to obtain the person j (xxm). Deprotection Can use a variety of standard procedures known to the industry ° Do not (such as "" protection of amines "" organic synthetic protective group ^

Edited by Greene and P.M.Wuts, Joshua 4,,,,,,,,,,,,,,,,,,,,, and 10 Willen & Sons, Willie & Sons, pp. 10-142, 309-405). 1 year, reaction figure 9: O: \ 87 \ 87131.DOC -25- 200424198

(XXIV) 〇

(XXVI)

〇

(XXVII) 〇

The nicotinate compound (X) can be prepared in the following reaction steps. In Reaction Figure 9, the pyridine compound (XXIV) is treated with n-butyllithium, followed by RfCOZ or R'COR '(where R'SCualkyl or benzyl and Z is halogen) to obtain compound (XXVI). This reaction can be carried out in a suitable reaction inert solvent. Suitable solvents include, for example, ethers such as THF, DME, diethyl ether, diisopropyl ether, diphenyl ether, and 1,4-dioxane. This reaction can be carried out at a temperature in the range of -100 to 50 ° C, usually -100 to 20 ° C, for a period of 5 minutes to 24 hours, usually 15 minutes to 8 hours. Alternatively, the compound (XXVI) can be prepared from a pyridine compound (XXIV) by carboxylation followed by esterification. The pyridine compound (XXIV) can be treated with n-O: \ 87 \ 87131.DOC -26- 200424198 butyllithium and then treated with carbon dioxide (gaseous or dry ice) to obtain a gallic acid compound (XXV). This reaction can be carried out in a suitable reaction inert solvent. Suitable solvents include, for example, ethers such as THF, DME, diethyl ether, diisopropyl ether monophenyl ether, and dioxane. This reaction can be carried out at a temperature of -100 to 50 ° C, usually 100 to 20 ° C gj for 5 minutes to 24 hours, usually 15 minutes to 8j. The compound (χχν) can be converted to compound (XXVI). The chemical conversion can be performed by a variety of standard procedures known to those in the industry (eg, organic synthetic protecting groups, 3rd edition, editors T.W.Green and P.G.M.Wuts, Wiley Technology, p. 373_377). Typical esterification can be carried out in the presence of a base in a suitable reaction inert solvent using a suitable Cw alkyl halide or fluorenyl halide. Suitable solvents include, for example, ethers such as THF, DME, diethyl ether, diisopropyl ether, diphenyl ether, DMF, DMS. , Heart dioxin. Appropriate tests include, for example, potassium carbonate, hammer carbonate, sodium bicarbonate, and DBU. This reaction can be at a temperature of from 100 to 200 ° C, usually from -10 to 100. (: The temperature is in the range of 1 to 72 hours, usually 2 to 60 hours. Esterification can also be performed in a suitable reaction inert solvent using trimethylsilyldiazomethane. Suitable solvents include, for example, methanol, benzene and toluene. This reaction can be carried out at a temperature ranging from -100 to 20 ° C, usually from 10 to 10 ° (rc '), for a period of from 1 minute to 72 hours, usually from 0.5 to 60 hours. Esterification can also use diazo. Methane is carried out in a reaction-inert solvent. Suitable solvents include, for example, diethyl ether. Such a reaction can be carried out at a temperature in the range of 100 to 200 (rc, usually -50 to 100c) for i minutes to 72 hours, usually The time is from 0 to 60 hours. In addition, the esterification reaction can be performed in the presence of a coupling agent and a tertiary amine in a suitable solvent using R, OH. Suitable coupling agents include, for example, dcC, WSc, cyanophosphonic acid diiso Propyl ester (DIPC), 301 > 〇: 1 and 2,4,6, trigas benzamidine chloride.

O: \ 87 \ 87131.DOC -27- 200424198 Suitable tertiary amines include, for example, diisopropylethylamine, triethylamine. Suitable solvents include, for example, DMF, THF, diethyl ether, DME, dichloromethane, and 2-dichloroethane. This reaction can range from-丨 ㈧ to] ^^, usually from -50 to 100. A temperature in the range of 〇 is carried out for 1 minute to 100 hours, usually for a period of time ranging from 0.5 to 80 hours. When R1 is an i atom, the compound (χχνι) can be treated with dentin or N_dentified succinimide or SELECTFLUOR (registered trademark) under appropriate conditions to obtain the compound (χχνι), Wherein R1 is a halogen atom. This reaction can be performed in a suitable reaction inert solvent, such as carboxylic acids (such as acetic acid, propionic acid, and butyric acid); functional hydrocarbons such as chloroform, dichloroethane, and 1,2-dichloroethane; Amidoamines * DMf and trimethylamine hexamethylphosphate; sulfoxides such as DMSO, acetonitrile; benzene, toluene, xylene; and pyridine. This reaction can be carried out at a temperature in the range of 0 to 8 ° C, usually 25 to 70 °, for 5 minutes to 24 hours, usually 15 minutes to 8 hours. Then the compound (XXVII) is bonded to Deprotection to obtain compound (X). Deprotection can be performed in the presence of a test (such as potassium third butoxide, sodium ethoxide, and sodium hydroxide) or in the presence of an acid (such as hydrochloric acid and sulfuric acid). Deprotection can be appropriate The reaction inert solvent, such as methanol, is carried out at 25 to 8 ° C, usually 50 to 65. The range is: 10 minutes to 24 hours, usually 30 minutes to 10 hours. In addition, the initial formula (XXIV ) Compounds are known or can be prepared from known compounds according to procedures known to those skilled in the art, for example, Journal of the American Chemical Society (1986), 108 (12), 3310-18. The present invention includes the salt form of compound VII as described above. As long as the microphone of the present invention

Zolopyridine compounds are basic compounds, and can form a wide variety of different salts with a variety of inorganic or organic acids. DO: \ 87 \ 87131.DOC -28 · 200424198 can be used to prepare compounds of the aforementioned formula odor σ and σ test. The pharmaceutically acceptable acid addition salt is an acid that can form a non-toxic acid addition salt. This kind of salt is also a salt containing a pharmaceutically acceptable anion, such as a gaseous substance, a bromide. , Iodide, nitrate, sulfate or bisulfate, SSL or acidic phosphonate, acetate, lactate, citrate or acid beech tartrate, tartrate or hydrogen tartrate, succinate, malate, Fumarate, gluconate, salcatenate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (ie, 1, 1,- Methylene-fluorene_ (2_hydroxy_3_fluorene formate)). Acid addition salts can be prepared by conventional procedures. The compound of formula (I) of the present invention contains one or more asymmetric centers. In this way, the compounds can exist in separate (+)-and optically active forms and their racemic forms. The invention includes all such forms within its scope. Individual isomers can be obtained by known methods, such as optically selective reactions or chromatographic separations in the presence of the end product or its intermediates. In addition, when the compound of the present invention forms a hydrate or solvate, the hydrate or solvate also falls within the scope of the present invention. The imidazopyridine compound of the present invention has a 5-HT4 receptor binding activity (such as agonist activity or antagonist activity), and thus can be used in mammals, especially humans, to treat or prevent gastroesophageal reflux disease, gastrointestinal disease, and gastric motility disorders. , Non-cancerous dyspepsia, functional dyspepsia, irritable bowel syndrome, constipation, indigestion, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, Vomiting, migraine, neurological disorders, pain and cardiovascular conditions such as heart failure and arrhythmia. O: \ 87 \ 87131.DOC -29- 200424198 The compound of the present invention is preferably used in combination with one or more other therapeutic ingredients selected from antibiotics, antifungals and antivirals. Method for evaluating biological activity: The 5-HT4 receptor binding affinity of the compound of the present invention was measured by the following procedure. Membrane preparation (pig heads are supplied by the slaughterhouse. Cut striatum tissue, weigh, and apply a Polytron homogenizer at 15 times volume, 50 mM ice-cold HEPES (pH 7.5) _ homogenization (full speed 30 Seconds). The suspension was centrifuged at 48,000 g and 4 ° C for 15 minutes. As a result, the pellets were resuspended in an appropriate volume of 50 mM ice-cold HEPES, divided into whole portions, and stored at -80 ° C until use. Supplied by the slaughterhouse. Cut the striatum, weigh it, and homogenize the Yu Puli Chong homogenizer at a volume of 50 × 111% with ice cold 1 ^-: «(: 1 (? 117.4) homogenization (full speed 3 0 seconds). The suspension was centrifuged at 20,000 g and 4 ° C for 30 minutes. As a result, the pellets were resuspended in 50 Mm Tris-HCl with 15 times the volume, and homogenized and centrifuged again in the same way. The final pellets were resuspended in an appropriate The volume of 50 · mMTris-HCl was dispensed into whole portions and stored at -80 ° C until use. Cerebral cortical tissue was removed from male Sprague-Dawley (SD) rats (Japanese SLC), weighed and placed in 10 Volume 50 mM ice-cold Tris-HCl (pH 7.5). Yu Lizong_ Homogenizer homogenization (30 seconds full speed), followed by 48,000 g and 4T: centrifugation for 15 minutes · minutes The resulting pellets were resuspended in 50 mM Tris-HCl, homogenized and centrifuged again in the same manner. The final pellets were resuspended in an appropriate volume of 50 mM Ti: is-HCl, distributed into whole portions, and stored at -80 ° C until the time of use. The protein concentration of the homogenate is determined by the Bradford method or the BCA protein method O: \ 87 \ 87131.DOC -30- 200424198 (Pierce), and the BSA is used as the standard. Analytical compounds are combined with the assay. The affinity for porcine or bovine 5-HT4 receptors and rat SHU receptors is evaluated using radiolabeled specific ligands, such as GR 1 13808 ({1- [2- (methylsulfonate Fluorenyl) ethylpiperidinyl} [methyl-H] -1H-indole-3-carboxylic acid ester) and BRL 43694 (1-methyl-N- (9_ [methylazabicyclopyridinamide) ). The compound was suspended with 25_1OOpM [3H] -GR 1 13808 (Amersham) and .6-1 mg of porcine or bovine striatum membrane protein in 50 mM of a final volume of 08- 丨 ml Tris-HCl (pH 7.5) co-culture. Non-specific binding was determined using 10-50 μM 5-ΗΤ. 0.3 nM [3H] -BRL 43694 (ΝΕΝ) binding system using 400 micrograms of rat cerebral cortical membrane protein suspension In a final volume 5〇〇 microliters of 50 mM (pH 7.5) measured Tris-HCl. Non-specific binding lines were determined using 105-HT. The plates were incubated on a plate shaker for 30 minutes at room temperature. The assay was performed using a Brandell cell harvester through a Wallac-B membrane [pre-soaked in 0.2% poly (ethyleneimine)] at 4 ° C for rapid filtration 60-90 Minutes and abort the assay. The filter was washed three times with 1 ml of ice-cold 50 mM HEPES, and dried in a microwave or at room temperature. Bagged and heated with a meltilex scintillator (Wallock) or immersed in BetaplateScint (Wallock). Receptor-bound radioactivity is quantified using a large spot counter, a beta plate counter (Wallock), or an LS counter (Packard). Human 5-HT4 binding O: \ 87 \ 87131.DOC -31-200424198 Human 5-HT4 (d) was infected with HEK293 cells and prepared and grown indoors. The resulting cells were collected and suspended in a 50 mM HEPES (pH 7.4, 4 ° C) supplemented with a protease inhibitor mixed solution (Boehringer, 1 ·· 1000 dilution) using a hand-held Borichon PT 1200 to disintegrate. The resolver was set to full speed power and homogenized on ice for 30 seconds. The homogenate was centrifuged at 40,000 X g for 30 minutes at 4 ° C. The pellets were then resuspended in 50 mM HEPES (pH 7.4 at 4 ° C), detached again in the same manner, and re-centred. The final pellets were resuspended in an appropriate volume of 50 mM HEPES (pH 7.4 ^ at 25 ° C), homogenized, divided into whole portions and stored at -80 ° C until use. The entire membrane was measured for protein concentration using the BC A Protein Assay Kit (Pierce) and the ARVOsx Plate Reader (Wallock). For binding experiments, 25 microliters of test compound and 25 microliters of [3H] -GR113808 (Amosan Corporation, final concentration 0.2 nM) and 150 microliters of membrane homogenate and WGA-SPA beads (Amosan Corporation) ) Suspension solution (10 μg protein and 1 mg SPA beads / well) was incubated at room temperature for 60 minutes. Non-specific binding was determined at a final concentration of 1 μΜ 01011113 808 (Torris (1 \) (^ 8)). The culture was terminated by centrifugation at 1000 rpm. Receptor-bound radioactivity was quantified using a microbetta well plate counter (Wallock). Functional assay analysis: The 5-HT4 receptor is present in the rat esophagus, and the ability of the 5-HT4 receptor to show partial excitatory effects in TMM products is reported in the reference (refer to GS Baxter et al., Naunyn_Schmiedeberg, Arch Pharmacol (1991) 343: 439-446; M. Yukiko et al., Jpet (1997) 283: 1000-1008; and JJ Reeves et al., British Journal of Pharmacology (1991) 103 · 1067-1072). Partial excimer activity was measured according to the following procedure. O: \ 87 \ 87131.DOC -32- 200424198 Male SD rats (Charles River) weighed 25-30 grams, and the rats were sacrificed and decapitated. The esophagus is cut into the trachea immediately from the stomach (including the distal end of the stomach) and placed in fresh Krebs solution. The exoskeletal muscle layer is stripped from the underlying smooth muscle layer using nickel (stomach to trachea direction). The remaining internal smooth muscle tube is called TMM. The TMM was cut from the original "end of the stomach" to 2 cm, and the rest was discarded. The TMMs were installed in a 5 ml organ bath in the longitudinal direction in the entire "open" tube. The organ bath was filled with warm (32.0) aeration Krebs solution. The tissue was placed under an initial tension of 750 mg and allowed to equilibrate for 6 G minutes. During the equilibration period, the tissue was re-tensioned twice at 15-minute intervals. During this period, the flow rate of the pump was set to 2 ml / min. After the equilibration, the pump was closed. The tissue was exposed! Reach a stable contraction platform within 15 minutes. Tissue contact 1 μM 5-HT (used to prime the tissue). The tissue is quite fast, and relaxes in response to 5. -Once the maximum relaxation occurs, take a measurement, wash the tissue at the maximum rate (66 ml / min) for at least] minutes, and wash until returning to the original baseline (pre-Kabaco and 5_ΗΤ) (usually after the initial balance, the baseline Value drops below the original value). The pump flow rate was reduced to 2 ml / min, and the tissue was left for 60 minutes. In semi-logarithmic increments, a progressive wave-effect-curve (CEC) of 5-11 d across a range of 0_1 ηM to 1 μM is formed (a 5_ητ curve for data analysis. The contact time between doses is 3 Minutes, or contact to establish a platform. As the 5-ΗΤ concentration in the bath increases, the tissue responds more quickly. The tissues can be washed as fast as possible (at the maximum rate) to avoid desensitization of the recipient.

O: \ 87 \ 87131.DOC -33-200424198 The rate was reduced to 2 ml / min, and the tissue was maintained for 60 minutes. A second CEC was performed on the 5-HT (for time-controlled tissues), another 5-HT4 agonist (standard), or a test compound (curve 2 for data analysis). The contact time of other 5-HT4 exciters and test compounds varies, and is adjusted based on the response of individual tissues to specific agents. High concentration (1 μM) 5-HT4 antagonist (SB203, 186: 1H-aquiline-3-carboxylic acid, 2- (1-piperidinyl) ethyl ester, Torris, in tissues exposed to test compound ) Add to the bath after adding the final concentration of test compound. To find out whether the relaxation (if any) induced by the stimulant is reversible. SB 203,186 reverses the relaxation induced by 5-HT and restores the original degree of tension induced by carbachol. The excimer activity of the test compounds was confirmed by incubation with tissues and 100 nM standard 5HT4 antagonists (such as SB 203,186). Add SB 203,186 to the bath 5 minutes before the addition of Kabak before curve 2. The tissues used for data analysis must be "paired", in other words, the test compound is compared in one tissue in the absence of SB 203,186 with the test compound in another tissue in the presence of SB 203,186. Curve 3 could not be performed, in other words, 5-HT curve 1, followed by test compound curve 2 (-SB 203,186), and then test compound curve 3 (+ SB 203,186). Human 5-HT4⑷ metastatically infected HEK293 cells have increased cAMP induced by agonists. Human 5-HT4⑷ metastatically infected HEK293 cell lines were established indoors. Cells were grown in DMEM at 37 ° C and 5% carbon dioxide, DMEM supplemented with 10% FCS, 20 mM HEPES (pH 7.4), 200 μg / ml hygromycin B (Gibco), 100 Units / ml penicillin O: \ 87 \ 87131.DOC -34- 200424198 and 100 μl / ml streptomycin. Cells grow to 60-80% confluence. The day before the compound treatment, the FCS (Gibco) after dialysis replaced the normal FCS and the cells were cultured overnight. Compounds were prepared in 96-well plates (12.5 μl / well). Cells were harvested with PBS / 1 mM EDTA, centrifuged and strips were washed with PBS. At the beginning of the assay, cell pellets were resuspended at 1.6 x 105 cells / ml in 20 mM HEPES, 10 μM pargyline (Sigma) and 1 mM 3-isobutyl-1 -DMEM of methylxanthine (Sigma) and left at room temperature for 15 minutes. The reaction was initiated by adding cells to the well plate (12.5 μl / well). After 15 minutes of incubation at room temperature, 1% Triton X-100 was added to stop the reaction (25 μl / well), and the wells were left at room temperature for 30 minutes. According to the manufacturer's instructions, the fluorescent-based cAMP (Schering) detection is performed in uniform time analysis. ARVOsx multi-label counter (Wallock) is used to measure HTRF (laser 320 nm, light emission 665 nm / 620 nm, delay time 50 microseconds, window time 400 microseconds). The data are based on the fluorescence intensity ratio analysis of 620nm and 665nm of each well, and the cAMP quantification was performed using the cAMP standard curve. The increase in cAMP production derived from various compounds was regulated to 1000 nM serotonin (Sigma) cAMP production. Human dofetilide combined with human HERG metastasis infected HEK293S cell line was prepared and grown indoors. The collected cells were suspended in 50 mM THs-HCl (pH 7.4 at 4 ° C) and homogenized on ice for 20 seconds at full power using a hand-held Boli Chung PT 1200 disintegrator. The homogenate was centrifuged at 48,000 X g for 20 minutes at 4 ° C. Then the pellet O: \ 87 \ 87131.DOC -35- 200424198 was resuspended, homogenized and centrifuged again in the same way. The final pellets were suspended in an appropriate volume of 50 mM Tris-HCl, 10 mM KCH, 1 mM MgCl2 (pH 7.4 at 4 ° C), homogenized and distributed into whole portions and stored at -80 ° C until use. One membrane was used for protein concentration determination using the BCA Protein Assay Kit (Pierce) and ARVOsx Plate Reader (Wallock). The combined assay was performed in a 96-well plate with a total volume of 200 microliters. Twenty microliters of the test compound was co-cultured with 20 microliters of [3H] -Dofetilyl (Amosan Corporation, final concentration 5 nM) and 160 microliters of molar homogenate (25 microgram protein) at room temperature for 60 minutes. Non-specific binding was measured at a final concentration of 10 μM dofetilide. Using a Skatron cell harvester, filtered through a 0.5% pre-soaked GF / B beta plate using 50 mM Tris, HCn, 10 mM KC, 1 mM MgCl2, pH 7.4 at 4 ° C The reaction was terminated by rapid vacuum filtration. The filter was dried and placed in a sample bag and filled with beta well scintillator. The radioactivity incorporated into the filter was counted using a Valocbet orifice plate counter.

Iherg Assay 4 HEK 293 cells stably expressing HERG potassium channels are used for electrophysiological studies. Methods for stably transferring HEK cells to infect such channels can be found elsewhere (Z. Zhou et al., 1998, Biophysical Period U, 74, 230-241). Before the day of the experiment, the cells were harvested from the culture flask and seeded on glass coverslips in standard MEM medium containing 10% FCS. The inoculated cells were stored in an incubator at 37 ° C under a 95% oxygen / 5% carbon dioxide atmosphere. Study the cells 15-28 hours after harvest. The HERG current system is researched using the whole-cell mode using standard patch fixture technology. O: \ 87 \ 87131.DOC -36- 200424198. During the experiment, the cells were superfused with a standard external solution. The composition of the solution was as follows (mM), · NaC BU 130; KC BU 4, CaCl2, 2; MgCl2, j; glucose, 10; adjusted to 卩 with sodium hydroxide ; ^ 7 · 4. Use a patch clamp amplifier and a patch burette for whole-cell recording. The burette has a resistance of 1-3 million ohms when filled with a standard internal solution with the following composition (mM); KC1,130; MgATP, 5; MgC12, 1.0; HEPES, 10; EGTA 5, ^ adjusted to ρΗ 7 · 2 using potassium hydroxide. Only cells with access resistances below 15 million ohms: ohms and 4 ohms greater than 1 billion ohms are accepted for further research. Apply the series resistance error to a maximum of 80%. No leak deductions were made. However, the acceptable access resistance is determined by the current recorded and the series resistance compensation level that can be safely used. After achieving the whole-cell configuration and sufficient cell dialysis time (greater than 5 minutes) with Diriguan solution, the & quasi-voltage scheme was applied to the cells to stimulate membrane current. The voltage scheme is as follows. The membrane was depolarized from a holding potential of -80 pen volts to +20 millivolts for a time of 1,000 milliseconds. The ramp-down voltage (rate 0.5 millivolts milliseconds -1) is then returned to the sustain packet. A voltage scheme was continuously applied to the cells every 4 seconds (0.25 Hz) throughout the experiment. The amplitude of the spike μ, which was quoted near -40 millivolts during the slope, was measured. Once a stable excited current response was obtained in the external solution, the vehicle (0.5% DMSO in a standard external solution) was applied by a pulsating pump for 10-20 minutes. Assuming that the amplitude of the current response of the excitation is very small under the vehicle control conditions, the square compound 0 0 • 3, 1, 3, μ μ test compound experienced 10 minutes. The 10-minute interval includes the time when the solution is supplied from the solution storage tank to the recording room via the pump. After the drug concentration in the room reached the intended concentration, the cells were exposed to the compound's cardiac fluid for more than 5 minutes. Has a reversible situation. Finally, the cells are exposed

O: \ 87 \ 87131.DOC -37- 200424198 at high doses of dofetilide (5 μΜ) to evaluate insensitive endogenous currents Dofetilide is a specific IKr blocking agent. All experiments were performed at room temperature (23 rc). The excited membrane current is recorded on the computer's online record at 5 (KM_ 赫 ⑽⑽ 地), and at 2 kHz, the money is reduced by A || The peak current amplitude, which appears at about -40 millivolts, is measured offline on a computer. The arithmetic mean of 10 amplitude values is calculated under controlled conditions in the presence of drugs. The percentage reduction of In in each experiment was calculated using the following formula _: IN = u.wIg), where Id is the average secondary value in the presence of the drug 4 is the average current value under the control conditions. Pair: Separate time-matched controls. · The average value of Gu Guan's test is defined as research. The test results are summarized as follows:

O: \ 87 \ 87131.DOC 38 · 200424198 Chemical structural formula 5ΗΤ4 binds Ki [nM; | Dofetilide binds Ki [μΜ] ΤΙ (Dofetilide / 5HT4) Η Compound A 1.2 2.3 1,900 C, X ^ T ^ H ^ T ^ Η2N Human N, ν Η Compound B 4.6 6.0 1,300 χ0χ1, Η Λ Compound of Example 1 of the present invention 0.82 5.75 7,000 O: \ 87 \ 87131.DOC -39- 200424198

O: \ 87 \ 87131.DOC -40- 200424198 x6u 2.0 > 24.0 > 12,000 1 IN s The compound of Example 5 of the present invention (wherein 11 is {Dofetilide bound KiOM] / 5HT4 bound Ki [nM] xl000}) The compounds of Examples 1-5 show TI values in the range of 5000-1800, and comparative compounds with similar structures and B show TI values of 丨, 900 and丨, 300. The formula (I) of the present invention has miso. Certain compounds can be administered to mammals orally, parenterally or with a local route. It is usually most desirable that the compound be administered to the class `` 3 mg to 750 mg daily, preferably 1 G mg to 5 mg mg per day, '' but the dose will vary depending on the weight and condition of the individual being treated, and the condition of the treatment And the specific route of administration chosen. However, for example, a daily dose of G.G. to 6 mg to 2 mg per gram of body weight is most suitable for the treatment of inflammation. The compound of the present invention can be administered alone, ZA # Μ Μ-^ 4,-, or, and, and 3 medically acceptable carrier diluents, diluents, or any other means, ^ ^^ administration, This administration can be ordered for single deaf or multiple doses. Especially this invention

. The novel therapeutics can be a wide variety of

Dosage form is administered as 'the invention is new', and it is not possible to combine it with a 3 M member / α therapeutic agent, which can be used in combination with a variety of pharmaceutically acceptable N-loading agents, gelatin powders, and sprays. , Cream: 3 tablets for oral use, buccal tablets, hard candies, pastes, lotions, ointments, water; raw materials: suppositories, suppositories, gumming agents, gelling agents, aqueous suspensions, injection solutions,

O: \ 87 \ 87131.DOC -41 ^ 200424198 Sugar ~ ’I and other dosage forms. Such carriers include solid carriers or fillers, sterile aqueous media, and various non-toxic organic solvents. In addition, oral pharmaceutical compositions can be used as supplements and / or flavors. Generally, the therapeutically effective compound of the present invention is present in such a dosage form in a range of 5% to 70% by weight, preferably 10% to 50% by weight. For oral administration, the lozenge contains a variety of excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dimethylglycine and a variety of disintegrating agents: such as corn flour and preferably corn starch, potato Starch or tapioca starch, alginic acid, a variety of complex osmium salts are used in combination with granulating binders such as polyvinyl eel residue, sucrose, gel and gum arabic. Lubricants such as stearic acid, laurel sulfate and talc are also very useful for tabletting purposes. Similar types of f-body compositions can also be used as fillers for gelatin capsules; preferred materials in this regard also include lactose or lactose and high molecular weight polyethylene glycols. When aqueous suspensions and / or tinctures are required for oral administration, the active ingredient can be combined with a variety of sweeteners or flavoring agents, colorants or dyes, and if necessary, emulsifiers and / or suspending agents can be combined with water, Diluents such as ethanol, propylene glycol, glycerin, and various combinations. — For parenteral administration, transdermal compounds can be used in sesame oil or peanut oil solutions or in aqueous glycerin solution. If there is a fH liquid-receiving agent, it is preferably buffered properly (preferably pH is greater than 8), and the liquid diluent is first adjusted to be taut. "The sex solution is for intravenous injection. The hydrazone solution is suitable for intra-articular injection, intramuscular injection and subcutaneous injection. The preparation of all these solutions under sterile conditions is easily accomplished by those skilled in the art using standard pharmaceutical techniques. In addition, the present invention is typically administered topically when treating skin inflammatory conditions

O: \ 87 \ 87131.DOC -42- 200424198, topical administration is preferably carried out via creams, tinctures, gels, pastes, ointments, etc. according to standard pharmaceutical specifications. EXAMPLES The present invention will exemplify the following non-limiting examples. Unless otherwise stated in the examples: all operations are performed at room temperature or ambient temperature, in other words, at a temperature in the range of 18-25 ° C; Evaporation is carried out using a rotary evaporator under reduced pressure with a bath temperature of up to 60 ° C. The reaction is monitored by thin layer chromatography (tic), and the reaction time is for illustration only; the listed melting points (mp) are not Corrected (polymorphism may lead to different melting points); the structural formula and purity of various isolated compounds are determined by at least one of the following techniques: tic (Merck Silicone 60 F254 pre-coated TLC plate or Grams of NH2 F254s pre-coated HPTLC plates), mass spectrometry, nuclear magnetic resonance (NMR), infrared absorption spectroscopy (IR) or microanalysis. Yields are for illustration purposes only. Rapid column chromatography uses low resolution mass spectrometry using Merck Silicone 60 (230-400 mesh ASTM) or Fuji Chromatorex DU3050 (amine-based, 30-50 microns) Data (EI) were determined on an Automass 120 (JEOL) mass spectrometer. Low-resolution mass spectrometry (ESI) data were obtained on a Quattro II (Micromass) mass spectrometer. NMR data was measured at 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA300). Unless otherwise indicated, NMR data was measured using deuterated gas imitation (99.8% D) or dimethylarsine ( 99.9% D) as a solvent, compared with tetramethylene silane (TMS) as an internal standard, expressed in parts per million (ppm); the abbreviations used conventionally are: s = single peak, d = doublet, t = Three peaks, q = four peaks, 111 = many_, br = wide, etc. Infrared spectrum data was measured by Borrow Island O: \ 87 \ 87131.DOC -43- 200424198 Tianjin Infrared Spectrometer (IR-470). Optical rotation was measured using a JASCO DIP-370 digital polarimeter (Japanese Spectroscopy Corporation). Chemical symbols indicate common meanings; bp · (boiling point), mp · (melting point), 1 (liter), ml (ml), g (gram), mg (milligram), mol (mole), mmol (millimolar ), Eq · (equivalent). Example 1: 5-Amino-6-Ga-N-[(Isobutylpiperidin-4-yl) methyl] _2-fluorenimidazo [l, 2-a] pyridine-8-carboxyfluorene Amine Step 1,2,6- 贰 ΓΓ2,2-Dimethylpropylpropionyl) Amine 1 methyl nicotinate in a 5-liter 4-neck round-bottomed flask, the flask was immersed in ice-cold ethanol-isopropanol ( 13% isopropanol, -15 ° C) in the bath, in the 2,6-2 [(2,2-dimethylpropanyl) amino] pyridine (American Chemical Society Journal 1986, 108, 3310-3318, 126 g, 454 mmol) in a solution of anhydrous tetrahydrool (1.5 liters) under a nitrogen atmosphere (internal temperature maintained at -15 ° C to -5 ° C) for 6 hours from the dropping funnel (1 liter) 2.66 M n-butyllithium in hexane solution (598 ml) was added dropwise. The resulting solution was stirred at 0 ° C (internal temperature) under a nitrogen atmosphere for 12 hours. The formation of a yellow precipitate was observed. The suspension was then cooled to -15 ° C and dimethyl carbonate (194 mL ' 2.3 mmol) was added in one portion. The reaction solution was stirred at 0 ° C for 1 hour, and quenched with 1.5 liters of 1 N aqueous hydrochloric acid. The pH was controlled to about 4.5 by adding N aqueous hydrochloric acid, and then 600 ml of ethyl acetate was added. After the layers were separated, the organic layer was washed with 1 liter (0.2 N) of aqueous mouse sodium oxide (1 liter) and brine (500 ml). Each aqueous layer was extracted twice with ethyl acetate (300 ml). The combined organic layers were dried over sodium sulfate (about 300 g) and concentrated. The residue was diluted with diisopropyl ether (300 ml) and the solution was evaporated to remove residual ethyl acetate by azeotropic distillation. The residue was dissolved with gentle stirring at 60 ° C in diisopropyl ether (360 ml), and a small amount of the desired compound crystals (about 5 mg) was added as seed crystals. It was found that a gray-yellow precipitate was formed. The resulting suspension O: \ 87 \ 87131.DOC -44- 200424198 was cooled to room temperature (cooled to room temperature in 2 hours), and stirred at room temperature for 2 hours. The suspension was filtered through filter paper, and the filter cake was washed with diisopropyl ether (8 () ml). The solid was dehydrated at room temperature under reduced pressure to obtain the title compound (120 g, 358 mmol, 79%) as a gray-yellow solid. MS (EI) m / z: 335 (M +) H-NMR (CDC13) 3 ·· 1.32 (9Η, s), 1.35 (9Η, s), 3.93 (3Η, s), 8 · 04 (1Η, d, J = 8_8 Ηζ), 8.31 (1Η, d, J = 8.8 Ηζ), 9.32 (1Η, br s), 11 · 47 (1Η, br s). Step 2 '5-Chloro-2,6-fluorene "((2 ^^ methylpropylpropyl) amino) nicotine methylamine is cooler than 2,6-methyl [(2,2-monomethylpropylpropyl) ) Amine] The final test of methyl acid g (Example 1, step 1,186 g, 555 mmol) in a solution of anhydrous ν, N-difluorenimidine (930 ml) under a nitrogen atmosphere at 70 ° C (internal temperature), N-chlorobutaneimine (81.5 g, 610 mmol) was added dropwise from a dropping funnel (1 liter) to anhydrous N, N-dimethylformamidine over a period of 2-5 hours. A solution of amine (560 ml). The resulting yellowish yellow solution was stirred at 70 ° C for 2 hours and allowed to cool to room temperature. The reaction solution was subjected to gasification with 250 g of sodium hydroxide and 100 g of sodium bisulfite in a 3 liter aqueous solution, and extracted with a mixture of ethyl acetate and hexane (3 liters, 3: 1). After the layers were separated, the organic layer was washed with water (2 L), dehydrated with sodium sulfite (300 g) and evaporated. Isopropyl ether (1.4 liters) was added to the residual grey solid, and the resulting mixture was stirred at 60 ° C for 2 hours. After the mixture was cooled to room temperature, the mixture was filtered through filter paper and the filter cake was washed with isopropyl ether (200 ml) and dehydrated at room temperature under reduced pressure to obtain (153.9 g, 416 mmol) of the title compound as a white solid . MS (ESI +) m / z: 370 (M + 1) iH-NMR (CDCl3) 5 ·· 1.34 (18 H, s), 3.94 (3Η, s), 8.30 (1Η, s), O : \ 87 \ 87131.DOC -45- 200424198 8.51 (1Η, br s) 5 11 · 12 (1Η, br s). Jingli i ^ 2,6-diamino nicotinic acid methyl ester in 5-gas-2,6-fluorene [(2,2-dimethylpropanyl) amino group; | methyl nicotinate (implementation Example 1 'Step 2' 153.9 g, 416 millimoles) in methanol (1.5 liters) colorless > in the valley fluid ' At room temperature under a nitrogen atmosphere, a second butyric oxide was added dropwise over a period of 20 minutes. A solution of potassium (185 g, 1.65 mol) in methanol (500 ml). The second potassium butoxide is dissolved in methanol, which is an exothermic reaction, so the third potassium butoxide needs to be divided into several parts using ice-cold water within 2 hours and added to the methanol from the powder addition funnel. After the addition was completed, the reaction solution was stirred at a reflux temperature under a nitrogen atmosphere for 1 hour, and cooled to room temperature. The resulting suspension was evaporated to remove about 13 liters of methanol (about 700 ml of methanol remaining). Water (ι · 2 liters) was added to the mixture, and the mixture was stirred at room temperature using a water bath (the internal temperature was maintained at 20.0) for 1 hour, and then the resulting suspension was filtered through filter paper. The gray-yellow solid was dehydrated at 50 ° C under reduced pressure for 12 hours. 74.3 g (368.9 mmol, 89%) of the title compound were obtained as grayish yellow crystals.

Rf value: 0.28 (ethyl acetate / hexane = 1: 2). 1H-NMR (DMSO-d6) 5: 3.71 (3H5 s)? 6.77 (2H5 br s)? 6.94 (2H? Br s), 7.72 (1H, s) 〇 Step 4 '5 -amino-6 -gas- 2-A certain mouth rice ° sitting n, 2-al4bp fixed -8-heteroacid methyl g 2,6-diamino-5- gas in acid test vinegar (Example 1, step 3, 15 grams, 74.4 mmol), bromoacetone (10.4 ml, 112 mmol) and sodium iodide (16.7 g, 112 mmol) in methanol (700 ml) were stirred at reflux for 22 hours. Another 2.5 ml (33 mmol) of bromoacetone was added and stirring was continued for 24 hours. The reaction mixture was quenched with saturated aqueous solution, and the methanol was removed in vacuo. The residue was extracted with ethyl acetate (250 ml x 10), and a small amount of methanol was added to dissolve the organic solid O: \ 87 \ 87131.DOC -46- 200424198. The organic extract was dried over sodium sulfate and concentrated. The silica gel was eluted with dichloromethane / methanol (20: 1) and purified by column chromatography to obtain a dark brown solid. The solid was washed with ethyl acetate and filtered to obtain 10_5 g (43.9 mmol, 59%). Compound as a beige solid. MS (FAB) m / z: 240 (M + 1) 〇1H-NMR (DMSO-d6) 5: 2.34 (3H? S), 3.80 (3H? S), 7.70 (2H? Br s), 7.83 (1Η, s), 7.85 (1Η, s). Step 5, 5-Amino-6-chloro-2-methylsome indolofluorene fl, 2-al pyridin 5-amino-6-chloro-2 -methyl miso [i, 2-a] p Titanium-8-metanoic acid methyl vinegar (Example 1, step 4, 10.5 g, 43-9 mol) in 1 N lithium hydroxide (87.7 ml, 87.7 mol) in methanol (100 ml) Stir at reflux for 1 hour. After the solvent was removed in vacuo, the residue was suspended in water and adjusted to pH 4 by treating with 2 N hydrochloric acid. The obtained solid was filtered, washed with water and diethyl ether, heated with dehydration under vacuum to obtain 9.5 g (42.2 mmol, 96%) of the title compound as a brown solid. MS (EI) m / z: 225 (M +) 〇 1H-NMR (DMSO-d6) 5: 2.38 (3H5 s)? 7.88 (1H5 s)? 7.92 (1H, s)? 8.00 (2H, brS). No signal was observed from coh. Steps: 6′-Hydroxy-6-II-isobutylpyridin-4-yl) a 1-methyl-methyl ester box opened Π--8-borrowed with 5-amino-6-gas 2-Methylimidazopyridine-8-carboxylic acid (Example 1, step 5, 7.0 g, 31.0 mmol) in a suspension of n, N-dimethylformamide (140 ml) in a chamber Add warmly, -carbonyldiimidazole (60 g, 37.2 mmol). After 5 minutes of stirring, the temperature rose to 60. And stirring was continued for 25 hours.

O: \ 87 \ 87131.DOC -47- 200424198 Another 2.5 g (15.5 mmol) of 1,1, -carbonyldiimidazole was added at room temperature, and the mixture was stirred at this temperature for 40 minutes and at 60 ° C. 2 hours. Then (1-isobutylpiperidin-4-yl) methylamine (Bio-Organic Medicinal Chemistry, 1999, 7, 2271-2281, 6.3 g, 37.2 mmol) was added at room temperature. A solution of methylformamide (25 liters) was continuously stirred for 18 hours. The mixture was quenched with water (165 mL). The deposited plates were collected by filtration and the bars were washed with water (200 ml). The filtrate was extracted with ethyl acetate (150 ml x 2). The precipitate and organic extract are combined and concentrated. The residue was purified by column chromatography (alkaline silica) using ethyl acetate / hexane (丨: 丨 to 2 · · l) to obtain a gray-yellow solid (8.39 g), which was treated with ether (200 ml) ) Wash to obtain 7.3 g (19.4 mmol, 63%) of the title compound as a white solid. MS (EI) m / z: 377 (M +) 〇m.p_: 216-219〇C 0 IR (KBr) p: 3472, 3246, 2951, 2920, 1638, 1607, 1562, 1545, 1437, 1321, 1265 , 1148, 1101, 710 cm · 1. H-NMR (DMSO-d6) 8: 0.82 (6H, d, J = 6.6 Hz), 1.18_1.31 (2Η, m), 1.4 · 1-1 · 55 (1Η, m), 1 · 61-1 · 83 (5Η, m), 1.97 (2Η, d, J = 7.2 Hz), 2.37 (3H, s), 2.78-2 · 81 (2Η, m), 3.28 (2H, t , J = 6.0 Hz), 7_58 (2H, br s), 7.86 (1Η, s), 7.88 (1Η, s), 9.92 (1Η, br). Analytical calculated values for Ci9H28C1N50: c, 60.39; H, 7.47; N, 18.53. Found: C, 60.33; H, 7.68; N, 18.43. Example 2: 5-Amino-N-[(l-isobutylammonium-4-yl) methyl] _2-methylimidazo [l, 2-a] pyridine-8-carboxamide-5 Amine_6_chloro-N-[(l-isobutylammonidine-4-yl) fluorenyl] -2-methylimidazole O: \ 87 \ 87131.DOC -48- 200424198 and [l, 2- a] Pyridine-8-carboxamide (Example 1, step 6, 134 mg, 0.36 mmol), 10% palladium charcoal (67 mg) and ammonium formate (224 mg, 3.6 mmol) in methanol (5 Ml) was stirred at room temperature for 4 hours. The mixture was filtered through Celite liner, and the filtrate was concentrated. The residue was treated with 25% aqueous ammonia (10 mL), extracted with methane (20 mL x 2) and washed with brine (20 mL). Removal of the solvent gave 92.4 mg (0.37 mmol, 76%) of the title compound as a yellow amorphous powder. MS (EI) m / z: 343 (M +) 〇IR (KBr) p: 3327, 3180, 2953, 2924, 1638, 1558, 1516, 1431, 1290 cnT1 〇1H-NMR (DMSO-d6) 5: 0.83 ( 6H5 d5 J = 6.5 Hz), 1.17-1.32 (2H3 m), 1.4 · 0.54 (1Η, m), 1.61-1 · 85 (5Η, m), 1.99 (2Η, d , J = 7.3 Hz), 2.36 (3Η, s), 2.79-2 · 83 (2Η, m), 3.25-3 · 29 (2Η, m), 6.04 (1H, d, J = 8.1 Hz), 7.26 (2Η, br s), 7.68 (1H, s), 7.85 (1H, d, J = 8.1 Hz), 10.00 (1H, br). Analysis calculated for C19H29N50_0.05C4H802.0.5H20: C, 64.62; H, 8.59; N, 19.62. Found: C, 64.89; H, 8.64; N, 19.36. Example 3: 5-amino-6-chloro-N-{[1_ (3,3-dimethylbutyl) piperidin-4-yl] sulfanyl 2-ethylimidazo [i, 2- a] Pyridin-8-carboxamidine Step 2—1,5-amino-6 · Ga · 2-ethylimidazolo fl, 2-a " l Pyridine-8-acid methyl acetate The title compound is according to the Examples 1 The procedure described in step 4 was prepared from 2,6-diamino-5-chloro-34-pyridinecarboxylic acid phosphonium ester (Example 1, step 3) and 1-bromo-2-butanone. MS (EI) m / z: 253 (M +). O: \ 87 \ 87131.DOC -49- 200424198 lH-NMR (DMSO-d6) 5: 1.27 (3H? T? J = 7.5 Hz)? 2.72 (2H? Q? J = 7.5 Hz), 3.80 ( 3Η, s), 7.72 (2Η, s), 7.86 (1H, s), 7.87 (1H, s). Step 2 ′ 5-amino-6-gas-2-ethyl group. "The title compound of L2-alp ratio 17- 8-weilic acid was obtained from 5-amino-6-chloro-2 -ethylimidazo [l, 2-a] according to the procedure described in step 5 of Example 1. Preparation of pyridine-8-carboxylic acid methyl ester (Example 3, step 1). MS (EI) m / z: 239 (M +). 1H-NMR (DMSO-d6) 5: 1.27 (3H5 t5 J = 7.2 Hz), 2.74 (2H, q, Bu 7.2 Hz), 7.88 (1Η, s), 7.95 (1Η, s) . No signal from COOH was observed. Step 3 "_4 .- ({" (5-Amino-6-Ga_2-Ethyl-Toyosaki and "1,2-31 Eb-8-yl") Carboxyl-Amine 丨 Methyl V-Dipene-1 -Tertiary butyl pivalate 5-amino-6-chloro-2-ethylimidazo [i, 2-a] pyridine-8-carboxylic acid (Example 3, step 2, 10.0 g, 41.72 mmol), 4- (aminomethyl) piperidine-1.carboxamidine dibutyl g (J. prUgh, L. A. Birchenough and MS Egbertson, Synthesis Communications, 1992, 22, 2357- 60, 15.20 g, 70.93 mmoles), DEPC (10.76 ml, 70.93 mmoles) and diisopropylethylamine (18.17¾ liters, 104.4 mmoles) in N, N-dimethylformamide (267 ml) of this mixture was stirred at room temperature for 43 hours. The solvent was removed by evaporation. The residue was basified with aqueous sodium bicarbonate (40 ml) and extracted with dichloromethane (5 x 100 ml). Washed with brine, dehydrated with magnesium sulfate and concentrated in vacuo. The residue was subjected to flash chromatography and eluted with dichloromethane / methanol (100: 1 to 20: 1) to obtain 19.08 g (90%) of the title compound, Yellow oil. O: \ 87 \ 87131.DOC -50- 200424198 1H-NMR (CDC13) 5 1.35 (3H? T? J = 7.6 Hz)? 1.45 (9H5 s) 5 1.88 · 1 · 28 (5Η, m), 2.88-2 · 64 (2Η, m), 3 · 52-3 · 38 (2Η, m), 4.30-3.97 (4H, m), 5.17 (2H, br s), 7.21 (1H, s), 8.19 (1H, s), 10_21 (1H, bv). Steps 4 '5 : Amine_6-chloro-2 · ethyl_N · Γ-bite-4-its methyl) imidopyridine-8-carboxamide in 4-({[(5-amino-6-chloro -2 -Ethyl imid. [1,2, a] Say a bityl group) Amino group] Amino group} Methyl) piperidine-1-carboxylic acid third butyl ester (Example 3, Step 3, π · 71 g '31.44 mmol.) Concentrated hydrochloric acid (10 ml) was added to a stirred solution of 10% hydrochloric acid in methanol (314 ml). After stirring at room temperature for 26 hours, the mixture was concentrated in vacuo to about 50 ml. The residue It was alkalized with excess sodium carbonate, and then filtered to remove insoluble materials. The filtrate was concentrated by azeotropic distillation with ethanol, diluted with a mixture of methane and methanol (5: 1, 200 ml). The formed inorganic solid was removed by filtration again. The filtrate was removed by Concentrated in vacuo to obtain a gray-yellow amorphous material which was crystallized from ethanol to obtain 4.79 g (45%) of the title compound as an off-white solid. Obtained from the mother liquor 5.09 g (48%) of compound MS (ESI) m / z:. 336.17 (M + H) +, 334 · 14 (Μ-Η) ·. m.p. (TG / DTA): 153 ° C. IR (KBr) p ·· 3387, 3300, 3188, 2964, 1639, 1605, 1562, 1514 cm * 1 ° 1H-NMR (DMSO-d6) 5: 1.30-0.90 (2H, m)? 1.30 (3H, t ? J = 7.6 Hz), 1.74-1 · 50 (3Η, m), 2.55-2.36 (2H, m), 2.75 (2Η, q, J = 7.6 Hz), 3.04-2 · 86 (2Η, m), 3.27 (2H, t, J = 5.9 Hz), 7.86 (1Η, s), 7.94 (1Η, s), 10.05-9 · 94 (1Η, m) : \ 87 \ 87131.DOC -51-200424198 C16H22ClN502.5H20.0.8EtOH Analytical calculated value ·· C, 50.70; Η, 7.49; Ν, 16.80. Measured value c, 50.57; Η, 7.27; N, 16.80. Non-compliance, 5,51 Amidine di 6-chloro-N- {| Ί-Π. 3_dimethylbutane V 啶 啶 -4- 臬] ^ 丄 1.2-B. Ϋ ri ri.2- a ~ | Pyrimidin-8-carboxamide in 5-amino-6-chloro-2-ethyl-N- (piperidin-4-ylmethyl) imidazo [l, 2-a] pyridine-8 -Carboxamide (Example 3, step 4, 450 mg, 1.34 mmol) and 1-bromo-3,3-dimethylbutane (606 mg, 3.35 mmol) in N, N-dimethyl To the stirred mixture of methylformamide (6 ml) was added potassium carbonate (648 mg, 4.69 mmol) and sodium iodide (502 mg, 3.35 mmol). After stirring at 90 ° C for 42 hours, the reaction mixture was cooled and evaporated. The residue was diluted with methane (30 ml) and water (20 ml). The mixture was extracted with dichloromethane (2x30 ml). The combined extract was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to flash chromatography (NH-silica gel) and eluted with hexane / ethyl acetate (1: 1 to 1: 2) to obtain a brown solid (296 mg), which was recrystallized from ethyl acetate to obtain 191 mg (34%) of the title compound as a beige solid. MS (ESI) m / z: 420 (M + H) +, 418 (M · Η)-. m.p. (TG / DTA): 234 ° C. IR (KBr) 3136, 2947, 1636, 1607, 1558 cnT1. 1H-NMR (CDC13) 5: 0.89 (9H, s)? 1.36 (3H, t? J = 7.5 Hz) 5 1.98-1.36 (9H, m), 2.37-2 · 26 (2Η, m), 2 · 83 (2Η, q, J = 7.5 Hz), 3.02 · 2.92 (2H, m), 3.45 (2Η, t5 J = 6.2 Hz), 4.96 (2Η, bsv), 7.12 (1H, s) , 8.20 (1Η, s), 10.17 (1Η, bs). Analytical calculated values for C22H34C1N50: C, 62.91; H, 8.16; N, 16.68. Found: C, 62.71; H, 8.20; N, 16.62. O: \ 87 \ 87131.DOC -52- 200424198 methoxy-2-methylpropyl) Example 4 · 5-amino-6-chloro-2-ethyl-N-{[1- (2 -Methoxypiperidin-4-yl] methyl} imidazo [124] pyridine-8-carboxamide

Yupeng Magazine, 1998, Dibenzylamine (2.5ml, 41, 2492-2502, 3.0g, 13.1mmol), 13.1¾mol) and diisopropylethylamine (3.4ml, 197mmol) Mol) In a stirred mixture of monochloromethane (150 ml), PyBroP (mo. Ginseng-salrolidyl-hexafluorophosphate scale) (61 g, 15.7 mmol) was added at 0 °. The mixture was stirred at ambient temperature for 18 hours, and then dissolved in dichloromethane and water. After extraction with dichloromethane, the combined organic phases were dehydrated with magnesium sulfate and concentrated. The residue was eluted with silica gel, hexane / ethyl acetate (6: 1), and purified by flash chromatography to obtain 4.0 g (7 5%) of the standard pass compound as a colorless amorphous powder. W-NM ^ CDCIW: 1.43 (9Η, s), 1.5 (M · 74 (4Η, m), 1.78-1.95 (2H, m), 2.58-2 · 75 (2Η, m), 4 · 45-4 · 51 (1Η, m), 7.11-7 · 44 (1〇Ηm) 〇 Step 2 'N, N _ dihydrazine 定 ° __ 4-completed brewing amine at 4- [ (Dibenzylamino) carbonyl] sigmadin-1 -carboxylic acid third butyl ester (Example 4, step 1, 4.0 g, 10.0 mmol) in methanol (5 50 ml) was stirred In the solution, a 4 N solution of dioxane hydrochloride (80 ml, 32 mmol) was added at 0 ° C. The mixture was stirred for 6 hours and evaporated. The obtained amorphous substance was dissolved in aqueous ammonia, and the mixture was burned with dichloromethane. Extraction. The combined extracts were dehydrated and concentrated with sulfuric acid to obtain 3.0 g (99%) of the title compound as a colorless amorphous powder. MS (ESI) m / z: 309 (M + H) +, 307 (MH ), O: \ 87 \ 87131.DOC -53- 200424198 Step 3, N · N_Difluorenyl-N-pyridine-cardiomethyl) amine in lithium aluminum hydride (at least 80%, 1.50 g, 40 · 0 mmol) in a suspension of tetrahydrofuran (50 ml), and N, N-dibenzylpiperidine-4-carboxamide (Example 4, step 2, 3.08 , Was 0 · 10 mmol) in tetrahydrofuran (50 ml). The mixture was stirred at 0 ° C for 30 minutes and at 40 ° C for 4 hours. After cooling to 0 ° C, carefully add water (3.3 ml), 15% aqueous sodium hydroxide solution (3-3 ml) and then water (10 ml). The resulting mixture was filtered through a Shilite pad, and the filtrate was concentrated in vacuo to obtain 2.85 g (97%) of the title compound as a gray-yellow oil. MS (ESI) m / z: 295 (M + H) +, 293 (M-H). 1H-NMR (CDC13) 5: 0.90-1.10 (2H? M)? 1.70-1.92 (4H5m)? 2.20 (2H, d, J = 7.2 Hz), 2.78 (1Η, s), 2.86 ( 2Η, d, J = 11.5 Hz), 3.48 (4H, s), 7.16-7 · 35 (10Η, m). Calendar i 1- {4-Γ (Diamidoamino) fluorenyl group> Citral-1-yl} -2-methylpropan-2-ol N, N-dibenzyl phenyl-4- Methyl) amine (Example 4, step 3, 3.3 g, 11.21 mmol) and 2,2-dimethylethylene oxide (12.1 ml, 134.5 mmol) in methanol (40 ml) and tetrahydrofuran (5 ml) of the mixture was heated with stirring at 40 C for 17 hours. The volatile components were removed, and the residue was purified on an amine-based gel using hexane / ethyl acetate (50: 1) and purified by flash column chromatography to obtain 3.0 g (73%) of the title compound. Colorless amorphous substance. -MS (ESI) m / z: 367 (M + H) +.

Step — Step_5 'N, N-Dibenzylmethyl-2-methylpropanyl H group 1 methyl} amine in sodium hydride (about 60% in mineral oil, 342 mg, 8.6 mmol) Tetrahydrofuran O: \ 87 \ 87131.DOC -54 200424198 A suspension of a mixture of sulfan (20 ml) and N, N-dimethylformamide (10 ml) was added at 0C to 1- {4- [(Dibenzylamino) fluorenyl] piperidinyl 2-fluorenylpropan-2-ol (Example 4, step 4, 3.0 g, 8.2 mmol) in tetrahydrofuran (20¾ liters). After stirring for 30 minutes at the same temperature, 0.53 ml (8.6 mmol) of methane was added to the mixture. The mixture was stirred at ambient temperature for 3 days. The mixture was dissolved in ethyl acetate and water. After extraction with ethyl acetate, the combined organic phases were dehydrated with magnesium sulfate and concentrated. The residue was eluted on an amine gel using hexane / ethyl acetate (100: 1) and purified by flash column chromatography to obtain 0.76 g (24%) of the title compound as a colorless amorphous substance. MS (ESI) m / z: 381 (M + H) + 〇1H-NMR (CDC13) 5: 1.12 (6H5 s) 5 0.99-1.19 (2H, m)? 1.43-1.60 (1H, m), 1 · 69-1 · 74 (2Η, m), 2.01-2 · 11 (2Η, m), 2.1 · 1-2 · 26 (4Η, m), 2.84-2 · 91 (2Η, m), 3.18 (3Η, s), 3.50 (3Η, s), 7.18-7.37 (10H, m) 〇 Step 6 'Q- (2-methoxy-2-methylpropylVilidine-4 -A certain methyl group has N, N-dimethyl-N-{[1_ (2-methoxy-2_methylpropyl) methyl] 4-methyl] amine} (Example 4 Step 5,756 mg, 1.85 mmol) and ammonium formate (583 mg, 9.24 mmol) in a solution of methanol (40 ml) and water (15 ml), add 10% absolute / carbon at ambient temperature (1 85 mg). The mixture was heated at 80 ° C for 6 hours. After cooling, the mixture was filtered through a Hillet pad, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in dichloromethane and aqueous ammonia. Extracted with dichloromethane Then, the combined organic extracts were dehydrated and concentrated with magnesium sulfate to obtain 275 mg (66%) of the title compound as a gray-yellow oil. W-NMIUCDCIW: 1.15 (6Η, s), 1.17-1 · 26 (2Η, m ), 1.58-1.68 O: \ 87 \ 87131.DOC -55- 200424198 (1H, m), 2.05-2 · 19 (2Η, m), 2.28 (2Η, s), 2.53-2 · 56 (2Η, m), 2.90-2 · 98 (2Η, m), 3 20 (3Η, s). Step 7 '5-Amino-6-chloro-2 -ethoxy-N-{"1- (2-methoxy-2-methylpropyl) piperidine-4- 1-methyl} imidazo fl, 2-al pyridine-8-carboxamidine The title compound was prepared according to the procedure described in step 6 of Example 1, using 5-amino-6-amino-2-ethylimidazo [l , 2-a] E. stilbene-8-carboxylic acid (Example 3, step 2) and [1- (2-methoxy-2-methylpropyl) methyl-4-yl] methylamine ( Example 4, Step 6) Preparation: MS (ESI) m / z: 422 (M + H) +, 420 (MH), mp: 2110 ° C IR (KBr) p · 3466, 3250, 2955, 2930 , 2918, 1632, 1620, 1600, 1545, 1437, 1319, 1268, 1146, 1105, 998 cm-1. 1H-NMR (CDC13) 5: 1.16 (6H, s)? 1.35 (3H5 t, J = 7.5 Hz ), 1.71-1.76 (2H, m), 2.29 (2Η, s), 2.82 (2H, q, J = 7.5 Hz), 2.46 (3H, s), 2.93-2 · 97 (2Η, m ), 3.43 (2H, t, J = 6.4 Hz), 4.97 (2H, brs), 7.14 (1H, s), 8.19 (1H, s), 10.08 (1H, br). Analytical calculated values for C2iH32C1N5O2.0.5H2O: c, 59.14; H, 7.68; N, 16.42. Found: C, 59.03; H, 7.62; N, 16.24. Example 5 · 5-Amino-6-amino-2-methyl-N-{[1- (2-methoxy-2-amidinopropyl) amidin-4-yl] methyl} imidazole The benzo [i, 2-a] pyridine-8-carboxamidine title compound was prepared using 5-amino-6-chloro-2-methylimidazo [i, 2-a according to the procedure described in Example 1, step 6. ] Pyridine-8-carboxylic acid (Example 1, step 5) and [1- (2-fluorenyloxy-2-methylpropyl) piperidin-4-yl] fluorenylamine (Example 4, step 6 ) And prepared. O: \ 87 \ 87131.DOC -56- 200424198 MS (ESI) m / z: 408 (M + H) +, 406 (M-H) _. mp: 211 ° C 0 IR (KBr) p: 3470, 3342, 3208, 2940, 2918, 1655, 1601, 1555, 1545, 1437, 1319, 1288, 1266, 1147 cnT1 〇1H-NMR (CDC13) 5: 1.16 (6H, s) 5 1.39-1.47 (2H5 m)? 1.71-1.76 (2H, m), 2.16 (2H, t, J = 110.0 Hz), 2.29 (2H, s), 2.46 (3H, s) , 2.93-2 · 97 (2Η, m), 3.20 (3Η, s), 3.43 (2Η, t, J = 6.4 Hz), 4.97 (2Η, br s), 7.14 (1Η, s) 5 8 · 19 (1Η, s), 10.08 (1H, bi · s). Analysis calculated for C2: 58.89; H, 7.41; N, 17.17. Found: C, 58.62; H, 7.38; N, 16.93. Example 6: 5-Amino-6-Ga-N-{[l- (2,2-dimethylpropyl) piperidin-4-yl] methyl} -2-ethylimidazo [i , 2 — a] P than bite -8-Wei donamine buhui 1 '1- (2,2-dimethylpropyl) into pyridin_4_ bramidine to isopiperidine formamide (2 g, 15.6 mmol) and isovaleraldehyde (2.0 ml, 18.7 mmol) in a solution of tetrahydrofuran (200 ml). Titanium isopropoxide (IV) (4.6 ml, 15.6 mmol) was added. Stir under warm nitrogen for 21 hours. The solvent was removed, and the residue was dissolved in ethanol (60 ml), and sodium cyanoborohydride (1.6 g, 23.4 mmol) was added at room temperature. After stirring for 89 hours, water (30 ml) was added, the resulting precipitate was removed by filtration, and the filtrate was concentrated. The residue was treated with water (30¾ liters), assayed with 2v sodium hydroxide, extracted with dichloromethane (30 mL x 3) and washed with brine (30 mL). The organic extract was dehydrated with sodium sulfate and concentrated to obtain a white solid. The solid was in silica gel. Dichloromethane / methanol was used to deposit / synthesize the liquid (20: i: 〇 ;; extract, purified by flash column chromatography to obtain 715¾ g (23%) of the title compound as a white solid.

O: \ 87 \ 87131.DOC -57- 200424198 MS (ESI) m / z: 199 (M + 1) + 〇1H-NMR (CDC13) 5: 0.82 (9H5s) 5 1.52-1.60 (4H? M ) 5 1.91-2.01 (3H, m), 2.09-2.18 (2H, m), 2.72_2.76 (2H, m), 6.70 (1Η, br s), 7.24 (1H, br s) 2 '丄 Π —_ (2,2_Dimethylpropyl V Limulus _4_some 1methyl} amine in aluminum hydride (342 mg, 7.2 mmol) in tetrahydroocran (15 ml Into the suspension, tetrahydrofuran of 1- (2,2-dimethylpropyl) piperidine-4_carboxamide (Example 6, step 1,715 mg, 3.6 mmol) was added at 0 ° C. Solution (15 * liters). The mixture was stirred at 40 ° C for 2 hours, cooled to room temperature, quenched with sodium sulfate decahydrate and potassium fluoride. Filtered through a Schlitter pad and the filtrate was concentrated to obtain the crude title compound. Product (785 mg) as a colorless oil. MS (ESI) m / z: 185 (M + 1) + OH-NMR (CDC13) 5: 0.85 (9H? S) 5 1.11-1.28 (2H, m) 5 1.49-1.86 (5H, m), 2.12-2 · 19 (2Η, m), 2.54-2 · 56 (2Η, m), 2.78-2 · 81 (2Η, m), 3. · 67-3 · 69 (2Η, m). Fluoride-free 3,5-amine, group-6-aziridinylpropanyl] methyl} -2_ethylimidazolofl, 2_alpyridine · 8_ The title compound was prepared according to the procedure described in Example 1, step 6, using 5-amino-6-chloro-2-ethylimidazo [i, 2-a] pyridine-8-carboxylic acid (Example 3, procedure 2) and {[1- (2,2-dimethylpropyl) piperidin-4-yl] methyl} amine (Example 6, step 2). MS (ESI) m / z: 406 (M + l) +. mep. (TG / DTA): 252 ° C. IR (KBr) W 3470, 3142, 3086, 2949, 1636, 1605, 1578, O: \ 87 \ 87131.DOC -58-200424198 1560, 1543, 1516, 1466, 1358, 1339, 1271, 1229 cm-1. 1H-NMR (CDC13) 6: 0.85 (9H? S)? 1.36 (3H5 t5 J = 7.5 Hz) 5 1.37-1 · 49 (2Η, m), 1.52_1 · 66 (1Η, m), 1.71-1.75 (2Η, m), 2.02 (2Η, s) 5 2 · 16-2 · 24 (2Η, m), 2 · 80-2 · 87 (4Η, m), 3.4 · 1-3 · 45 (2Η, m), 5.00 (2H, br s), 7.16 (1Η, s), 8.20 (1H, s), 10.17 (1H, br). Anal. Calculated values for C21H32C1N50: c, 62.13; H, 7.95; N, 17.25. Found: C, 61.92; H, 7.94; N, 17.06. Example 7 · 5-amino-6-chloro-sense {[1- (2,2-dimethylpropyl) piperidin-4-yl] methylmethylimidazo [l, 2-a] The pyridine-8-carboxamidine title compound was prepared according to the procedure described in Example 1, Step 6 using 5-amino-6-gas-2-methylimidazo [l, 2-a] pyridine-8-carboxylic acid (implemented Example 1, step 5) and {[1- (2,2-dimethylpropyl) piperidin-4-yl] methyl} amine (Example 6, step 2) were prepared. MS (ESI) m / z: 392 (M + 1) +. m.p. (TG / DTA): 256 ° C. IR (KBr) p · 3302, 3144, 2951, 1638, 1605, 1564, 1543, 1516, 1433, 1321, 1285, 1267, 1231 cm-1. 1H-NMR (DMSO-d3) 5: 0.82 (9H3 s)? 1.23-1.42 (3H5 m)? 1.60-1 · 64 (2Η, m), 2.01 (2Η, s), 2.12-2 · 19 (2Η, m), 2.37 (3Η, s), 2.74-2 · 78 (2Η, m), 3.26-3 · 30 (2Η, m), 7.57 (2H, br s), 7.85 (1H, s), 7.87 (1H, s), 9.92 (1Η, br). Calculated for C20H3oC1N50.0.1H20: C, 61.01; H, 7.73; N, 17.79. Found: C, 60.67; H, 7.68; N, 17.53. Example 8 · 5-amino-6-chloro-N-{[1- (3-methoxy-3-methylbutyl) piperidine O: \ 87 \ 87131.DOC -59- 200424198 -4 -Yl] methyl} 2-methylimidazolouj-a] pyridine_8_carboxamimine stepper "'([[amino] 6_ 氪 _2_methylimide 4 # ri, 2_al pyridine -8-A) Carboxylic acid, amino group, methyl) oxidine-1 acid tert-butyl ester The title compound was prepared according to the procedure described in step 6 of Example 1 using 5-amino-6-amino-2-methylimidazole. Benz [ij-a] pyridine-8-carboxylic acid (Example 1, step 5) and 4- (aminomethyl) piperidine-i-carboxylic acid tert-butyl ester (j. Prugh, LA

Birchenough and M.S. Egbertson, Synthesis Communications, 1992, 22, 2357-60). MS (EI) m / z: 421 (M) +. H-NMR (CDC13) 5.1.06-1.84 (14H5 m) 5 2.44 (3H5 s) 5 2.58-2.85 (2H, m), 3.45 · 34 · 49 (2Η, m), 4 · 〇〇 · 4 22 (2Η, m), 5.84 (2H, s), 7.34 (1Η, s), 8.17 (1H, s), 10.17 (1H, br t, J = 5.7 Hz). Step 5: Amine_6U dimethyl-N-((Nine_4_some methyldazole 4 and "nai pyridine-8-carboxamide dihydrochloride 4-(((5_amino -6-Gas-2-methylimidazo [lha] pyridyl) carbonyl] amino} methyl) Hydroxyl-1-weileric acid third butyl ester (Example 8, step 丨, 151 g, 35.8 mmol Ear) and a mixture of concentrated hydrochloric acid (5 ml) and a 0% methanolic hydrochloric acid solution (150 ml) was stirred at room temperature for 12 hours. The solvent was removed in vacuo to 30 ml, and ether (100 liters) was added to the residue. The obtained Shen Dian was collected by filtration and washed with ethyl acetate to obtain 13.9 g (98%) of the title compound as a gray-yellow solid. MS (ESI) m / z: 322 (M + 1) +. ^ -NMRCDMSO-d ^ S: 1.39 -1.53 (2H5 m) 5 1.80-1.91 (3H5 m) 2.45 (3Η, s), 2.69-2 · 89 (2Η, xn), 3 · 22-3 · 26 (4η, called, (8H , M). O: \ 87 \ 87131.DOC -60- 200424198 BEI Wei 3 '5 · Amino-6-Ga-N- 丨 Π- (3 -methoxy_3_y butyl butyl bottom bit_4_ ~ 1methyl 丨 2-fluorenyl imidazolium "1,2-a > pyridin-8- #" The title compound was prepared according to the procedure described in step 3 of Example 3 from 5-amino-6-chloro -2-methyl-N- (piperidin-4-ylmethyl) imidazo [124] pyridine_8 _ Carboxamidine monohydrochloride (performed in Step 8 of Example 8 ') and 1_E-3-methoxy-3-methylbutane *. MS (ESI) m / z: 422 (M + 1 ) + 〇mp (TG / DTA): 199 ° C. IR (KBr) p: 3499, 3325, 3182, 2926, 1657, 1620, 1601, 1572, 1547, 1514, 1431, 1323, 1261, 1078, 721 cnT1 ： 1.16 (6H? S) 5 1.37-1.49 (2H5 m) 5 1.60-1.72 (3H, m), 1.82-1 · 86 (2Η, m), 1.91 · 1 · 99 (2Η, m ), 2.35-2 · 40 (2Η, m), 2.46 (3Η, s), 2.95 · 2 · 99 (2Η, m), 3.18 (3Η, s), 3.43-3.47 (2H, m), 5.03 (2Η, br S), 7.15 (1Η, s), 8.19 (1Η, s), 10 · 09 (1Η, br) oC21H32ClN502t2H20 Analytical calculated value: c, 59.27; H, 7.67; N '16.46. Found: c, 59.0; H, 7 66; n, 1619. * 1-Iodofluorenyl-methylolbutane was prepared in 3-methoxy-3-methyl-1-butanol (3 g, 25.3 mmol) in dichlorofluorene (1〇 0 ml) of the solution in 0. O Triphenylphosphine (7.3 g, 27.9 mmol), imidazole (1.9 g, 27.9 mmol) and iodine (71 g, 27.9 mmol) were added. this. The mixture was stirred at 0 C for 3 hours. Aqueous sodium sulfite (5 ml) and aqueous sodium lactate (100 ml) were added, and the mixture was extracted with dioxane (20 ml x 3). After removal of the core J, the residue was suspended in hexane and filtered. The filtrate was concentrated. Disability

O: \ 87 \ 87131.DOC -61-200424198 The residue was flash-chromatographed using hexane / ethyl acetate GOO: i) to obtain 684 mg (9%) of the title compound as a gray-yellow oil. 1H-NMR (CDC13) 6: 1.15 (6H5 s) 5 2.11-2.17 (2H, m), 3.15-3.21 (2H, m), 3.18 (3H, s).

Rf: 0.3 (hexane). Example 9: 5-amino-6-chloro-N-{[1- (3-methoxy-2,2-dimethylpropyl) piperidin-4-yl] methyl} 2-methyl Imidazolo [丨, 2_a] pyridine_8_carboxamido genus 1, {Π ··: :( 3-methoxypropyl_2,2_dimethylformylpropylzidine_4_yl1methylsome} Isopiperidinemidine (1.0 g, 8.0 mmol), 3-methoxy-2,2-dimethylpropionic acid (Japanese Chemical Society Bulletin 2001, 74, 1695 · 702, 1.1 G, 8.0 millimoles), 2_ (1fluorene-benzotriazole-1_yl) _1,1,3,3_tetramethylhexafluorophosphate urea (HBTU, 3.3 grams, 8.8 millimoles) and v A mixture of N-diisopropylethylamine (1.5 ml, 8.8 mmol) in N, N-dimethylformamide (8 ml) was stirred at room temperature for 18 hours. Water (8 ml) was added and the mixture Extract with ethyl acetate (20 ml x 6). Remove the solvent to obtain the crude product 1- (3-methoxy_2,2-dimethylpropanyl) piperidine-4-carboxamide, brown The crude product was dissolved in tetrahydrofuran (5 liters) at 0 ° C. and added to a suspension of trifluorofuran (2.26 g, 47.7 mmol) in tetrahydrofuran (15 ml). The mixture was at 40 ° C. 〇 Stir for 3 hours and quench with sodium sulfate decahydrate and fluorinated bell. Filtration through a Hilite pad and concentration of the filtrate gave 925 mg (54%) of the title compound as a colorless oil. MS (ESI) m / z: 215 (M + 1) + 〇: 0.83 (6H? S) 5 1.13-1.32 (2H5 m)? 1.52-1.80 (3H, m), 2.12-2 · 24 (4 ( , M), 2.53-2.55 (2H, m), 2.74-2 78 (2H, m), 3.09 (2Η, s), 3.30 (3Η, s). No signal from nh2 was observed. O: \ 87 \ 87131.DOC -62- 200424198 Step 2, 5-Amino-6-gas-N-Π1-Π-methylamino-2J-dimethylpropyl) piperidin-4-yl 1methyl The title compound is 5-amino-6-chloro-2-methylimidazo [according to the procedure described in step 1 of Example 1 1,2-a] pyridine-8-carboxylic acid (Example 1, step 5) and {[1- (3-methoxy-2,2-dimethylpropyl) piperidin-4-yl] methyl Amine (Example 9, step 1). MS (ESI) m / z: 422 (M + 1) +. m.p. (TG / DTA): 1990C 0 IR (KBr) j /: 3309, 3152, 2922, 2868, 1638, 1603, 1560, 1545, 1512, 1425, 1321, 1111, 718 cm · 1. 1H-NMR (CDC13) 5: 0.83 (6H? S) 5 1.34-1.46 (2H5 m) 5 1.53-1.65 (1H, m), 1.70 · 1 · 73 (2Η, m), 2.13 (2Η, s) ), 2.18-2 · 25 (2Η, m), 2.47 (3Η, s), 2.76-2 · 80 (2Η, m), 3.09 (2Η, s), 3.30 (3H, s), 3 · 41-3 · 46 (2Η, m), 4.98-5 · 07 (2Η, m), 7.16-7 · 19 (1Η, m), 8.20 (1H, s), 10 · 09 (1Η, br) Calculated analytical value of C21H32C1N502: c, 59.77; Η, 7.64; N, 16.60. Found: C, 59.47; H, 7.65; N, 16.55. O: \ 87 \ 87131.DOC 63-

Claims (1)

^ 424198 Patent application park: h —Species ⑴ compound: 〇 Wherein R1 represents a hydrogen atom or a halogen atom; R2 represents a methyl group or an ethyl group; the table does not contain a branched alkyl group having 3 to 6 carbon atoms or a group containing 3 to 6 substituted with a alkoxy group containing 1 to 6 carbon atoms An alkyl group having 1 carbon atom; when the terminal carbon atom of the alkyl group is substituted with the alkoxy group, the alkyl group is a branched alkyl group; and a pharmaceutically acceptable salt thereof. 2. The compound according to item 1 of the scope of patent application, wherein R1 represents a hydrogen atom or a gas atom. 3. As for the compound in the scope of application for item i, wherein R1 represents a chlorine atom. 4. If the scope of patent application is the first! A compound according to any one of 3 to 3, wherein "represents isobutyl group, third butyl group; and the alkynyl group of R is unsubstituted or substituted with methoxy group. 5. A compound as stated in the first patent range , Which is 5-amino_N-[(isobutyl piperidine_4-yl) methyl] _2_methylimidazopyridinecarboxamide and its salt. O: \ 87 \ 87131.DOC 200424198 Declaration The compound in the first item of the patent scope is 5-amino-6-chloroN {[1- (3,3-dimethylbutyl) piperidinyl] methylbuth-2-ethylimidazon, 2 -a] pyridine-8-carboxamidine and its salts. 7. The compound according to item 1 of the scope of patent application, which is 5-amino-6-gas 1ethyl N-{[ι 气 2-methoxy -2-methylpropyl) piperidin-4-yl] methyl 丨 imidazo [l, 2-a] pyridine-8-carboxamidine and its salts 8. Compounds as described in item 1 of the patent , Which is 5-amino-6-chloro-2-methyl N-{[1- (2-methoxy_2_methylpropyl) piperidine_4_yl] methyl 丨 imidazo H, 2-a] pyridine-8-carboxamidine and its salts. 9 · As the compound in the scope of application for the patent, it is a $ -amino group_cardiochloride (1 · isopropyl group _4 · group) Methyl] I methylimidosilyl, 2__ pyridine-8- Carboxamide and its salts 10.-A species for the treatment or prevention of gastroesophageal reflux disease, gastrointestinal diseases, gastric motility disorders, upper gastrointestinal motility disorders, non-ulcerative dyspepsia, functional dyspepsia, irritability Bowel syndrome, constipation, indigestion, esophagitis, gastroesophageal disease, nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, vomiting, migraine, neurological disease, pain, ischemic stroke, anxiety or A pharmaceutical composition for a cardiovascular disorder, comprising a therapeutically effective amount of a compound of formula (I): O: \ 87 \ 87131.DOC -2-200424198 where Han represents a gas atom or _ atom; R represents methyl or ethyl; R represents 3 to 6 substituted by alkoxy groups containing 3 to 6 carbon atoms An alkyl group of 1 carbon atom; but when the terminal carbon atom of the alkyl group is substituted with the alkyl group, the alkyl group is regarded as a branched alkyl group; Λ and a pharmaceutically acceptable salt thereof. 11-A method for treating or preventing a disease called a receptor-active agent in a mammalian subject, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I): R1 represents a hydrogen atom or a halogen atom; R2 represents a methyl group or an ethyl group; R3 represents a branched alkyl group having 3 to 6 carbon atoms or 3 to 6 groups substituted with an alkoxy group containing 1 to 6 carbon atoms A carbon atom alkyl group, but when the terminal carbon atom of the alkyl group is substituted with the alkoxy group, the alkyl group is a branched alkyl group; and a pharmaceutically acceptable salt thereof. O: \ 87 \ 87131.DOC -3-200424198 12 · —A kind of treatment or prevention of gastroesophageal reflux, dysentery, moon disease, gastrointestinal dysfunction, upper intestinal dysfunction, non-malignant malformation , Functional dyspepsia, irritable bowel syndrome, constipation, indigestion, esophagitis, gastroesophageal disease, ° nausea, central nervous system disease, Alzheimer's disease, cognitive impairment, vomiting, migraine, Formulas for neurological diseases, pain, gold deficiency stroke, anxiety or cardiovascular disorders include administration of a therapeutically effective amount of a compound of formula (I) to an individual: Where R represents a hydrogen atom or a halogen atom; R2 represents a methyl group or an ethyl group; R table does not include a division of 3 to 6 carbon atoms | — a radical and radical or an alkane containing 1 to 6 carbon atoms An oxy-substituted alkyl group having 3 to 6 carbon atoms; but when the terminal carbon atom of the alkyl group is regarded as a branched alkyl group; when the alkoxy group is substituted, the alkyl group and a pharmaceutically acceptable salt thereof. 13 · —Application of the compound of formula (I) · O: \ 87 \ 87131.DOC -4- 200424198 R1 represents a hydrogen atom or a halogen atom; R2 represents a methyl group or an ethyl group; R represents a branched oxyalkyl group containing 3 to β carbon atoms or a group containing 3 substituted by an alkoxy group containing 1 to 6 carbon atoms Alkyl groups of up to 6 carbon atoms; but when the terminal carbon atom of the alkyl group is replaced by the alkyloxy group, the alkyl group is a branched alkyl group; ~ ^ i and a pharmaceutically acceptable salt thereof; In the manufacture of a drug for mammals to treat or prevent diseases caused by 5-ht4 receptor active mediators. 14. If the application of the compound in item 13 of the scope of patent application is used, the compound δ disease is gastroesophageal reflux disease, gastrointestinal disease, gastric motility disorder, non-cancerous dystrophy, functional indigestion, Irritable bowel syndrome, constipation, poor dyslipidemia, esophagitis, gastroesophageal disease, ° nausea, middle sacral nervous system, Alzheimer's disease, cognitive impairment, vomiting, migraine, neuropathic pain, Ischemic stroke, anxiety or cardiovascular condition. O: \ 87 \ 87131.DOC -5- 200424198 柒 、 Designated representative map: (1) The designated representative map in this case is: (none) (II) Brief description of the component representative symbols in this representative map ... 捌, if there is a chemical formula in this case When revealing the chemical formula that best characterizes the invention: O: \ 87 \ 87131.DOC